Abuse resistant capsule

ABSTRACT

The present invention is directed to an immediate release and extended release capsule or capsule fill which mitigates the abuse of abuse-susceptible active pharmaceutical ingredients by direct intravenous injection. The fill comprises a parenteral abuse resistant liquid formulation which when mixed with water and heated, results in a turbid, viscous or bubbling mixture that is not injectable with a standard insulin syringe. The abuse-susceptible active pharmaceutical ingredient is selected from the group consisting of opiates, opioids, tranquilizers, stimulants and narcotics.

FIELD OF THE INVENTION

The present invention relates generally to an immediate release or anextended release capsule formulation that is resistant to parenteralabuse of abuse-susceptible active pharmaceutical ingredients such asopiates, opioids, tranquilizers, stimulants, and narcotics.

DESCRIPTION OF THE RELATED TECHNOLOGY

Many active pharmaceutical ingredients, in addition to having anexcellent activity in their appropriate application, also have potentialfor abuse, i.e. they can be used by an abuser to bring about effectsother than those intended. For example, opioid analgesics, which arehighly active in combating severe to very severe pain, are frequentlyused by abusers to induce a state of narcosis or euphoria. Typically, aparticular dose of an opioid analgesic is more potent when administeredparenterally as compared to the same dose administered orally. Onepopular mode of abuse of oral opioid formulations involves theextraction of the opioid from the dosage form, and the subsequentinjection of the opioid (using any suitable vehicle for injection suchas an insulin syringe) in order to achieve a “high”.

This abuse problem is well known to the pharmaceutical and medicalindustries, and various methods of obviating such abuse have beendevised.

U.S. Pat. No. 7,842,307 (to Purdue Pharma L.P.) discloses oral dosageforms comprising a therapeutically effective amount of an opioidanalgesic, an opioid antagonist and one or more pharmaceuticallyacceptable excipients. The dosage form further includes a gelling agentin an effective amount to impart a viscosity unsuitable foradministration selected from the group consisting of parenteral andnasal administration to a solubilized mixture formed when the dosageform is crushed and mixed with from about 0.5 to about 10 mL of anaqueous liquid. The active pharmaceutical ingredient that is suspendedin high viscosity solutions is unsuitable for abuse via intravenousinjections.

UK Patent Application GB 2 238 478 A (to Farmitalia Carlo Erba Ltd andRP Scherer Limited) is directed to a pharmaceutical unit dosage formwhich comprises a soft gelatin capsule shell or a two-piece hard gelatincapsule filled with a benzodiazepine (preferably temazepam) in a gelcomprising at least 63% of polyethylene glycol 600, at least 4% byweight of polyethylene glycol 4000 or 6000 and at least 21% by weight ofan intermediate polyethylene glycol. This purports to solve the abuseproblem by using a formulation that is too viscous to be expelled from asyringe.

U.S. Pat. No. 7,230,005 (to Controlled Chemicals, Inc.) is directed tosolving the abuse problem discussed above by converting the activepharmaceutical ingredient to a poorly absorbed ester pro drug or otherprodrug derivative prior to formulation. Mechanical processing of tabletor caplets containing the prodrug does not release the active API. Thetablets and capsule beads containing prodrugs or other drugs can beformulated with a sufficient amount of a thickening agent to impedeinappropriate intravenous administration of formulations that are notindicated for these modes of administration.

WO 2010/044842 A1 (to Univ. Tennessee) is directed to solving the abuseproblem by including an effective amount of embolizing agent (i.e.,coagulating agent) which causes the production of a solid or semi-solidembolus or blockage after tampering. Suitable examples of embolic agentsare thrombin, cellulose diacetate polymer, albumin, gelatin, fibrinogen,lactoglobulin, immunoglobulin, actin, acrylamide, polyacrylonitrile,polyurethane, polyvinylacetate, nitrocellulose and copolymers ofurethane/carbonate and copolymers of styrene/maleic acid and pHsensitive polymers consisting of copolymers of methyl and butylmethacrylate and dimethylaminoethylmethacrylates.

U.S. Pat. No. 8,202,542 (to TrisPharma) discloses a modified releasetablet formulation of an opioid drug bound to an ion exchange resin,coated with a hybrid coating comprising a barrier coating containing apolyvinyl acetate polymer and a plasticizer and an enteric polymer mixedtherewith.

WO 2013/003845 A1 (to Neos Therapeutics, LP) is directed to oral drugdosage forms designed to reduce the abuse potential of an oral dosageform of an opioid analgesic. The oral drug dosage form comprises a firstpopulation of drug-resin complex particles comprising an analgesicallyeffective amount of an opioid drug coated with a water-permeablediffusion barrier coating; and a second population of ion exchange-resincomplex particles comprising an aversive agent coated with a polymercoating sufficient to substantially prevent release of the aversiveagent under normal use conditions. The abuse problem is addressed byusing two different particles within the liquid or solid dosage form.

European Patent No. 1 611 880 B1 (to Altergon S.A.) is directed toovercoming the abuse problem by providing pharmaceutical compositions ofdrugs known as replacement narcotics used in drug addiction therapy,such as methadone and/or its salts, preferably its hydrochloride, in auniform soft-gel matrix to be taken orally without chewing. The uniformmatrix has the shape and size of a pill or capsule of a certainformulation. The formulation is entirely gelatinized, i.e., uniformlyincorporated within the soft-gel matrix.

US 2010/0099696 A1, is directed to an oral dosage formulation containinga therapeutically effective amount of a drug susceptible to abuse and aneffective amount of an embolizing agent which causes the production of asolid or semi-solid embolus or blockage after tampering. The embolizingagent is a pH dependent polymer such as methacrylate, cellulose basedpolymer, and phthalate.

U.S. Pat. No. 7,776,314 (to Grunenthal) relates to a solidadministration form, protected from parenteral abuse and containing atleast one viscosity-increasing agent in addition to one or more activesubstances that have parenteral abuse potential. The agent forms, when anecessary minimum amount of an aqueous liquid is added, on the basis ofan extract obtained from the administration form, a preferablyinjectable gel that remains visually distinct when introduced intoanother quantity of an aqueous liquid.

U.S. Pat. No. 7,510,726 (to Acura Pharmaceuticals, Inc.) relates to anabuse deterrent dosage form of opioids, wherein an analgesicallyeffective amount of opioid analgesic is combined with a polymer to forma matrix. The formation of a high-viscosity gel is a result of exposingthe solid dosage form to water.

U.S. Pat. No. 7,399,488 (to Collegium Pharmaceutical, Inc.) is directedto an abuse-deterrent pharmaceutical composition wherein a drug ismodified to increase its lipophilicity. In preferred embodiments themodified drug is homogeneously dispersed within microparticles composedof a material that is either slowly soluble or not soluble in water. Insome embodiments the drug containing microparticles or drug particlesare water insoluble, but enzymatically degradable by enzymes present inthe human gastrointestinal tract.

U.S. Patent Application Publication No. 2009/0215808 (to Durect Corp.)is directed to oral pharmaceutical composition that is abuse-resistant,and its use to deliver the active pharmaceutical ingredient.

US 2010/0249045 (to Theraquest Biosciences, Inc.) is directed to abuseresistant pharmaceutical compositions of opioids and extended releasepharmaceutical compositions. All of the formulations appear to be forcaplets.

WO 2010/105672 A1 (to EvonikRöhm GmbH) relates to a controlled releasepharmaceutical composition, comprising a core comprising apharmaceutical active ingredient, whereby the core is coated by anethanol resistance conferring coating layer which has the effect ofconferring the release profile of the pharmaceutical active ingredientto be resistant against the influence of ethanol. The carious coatingtechniques and formulations related thereto are taught.

WO 2010/066034 A1 (to Paladin Labs Inc.) is directed to novel narcoticformulations having a decreased injection abuse potential. An oralpharmaceutical formulation is provided that makes the extraction of theactive pharmaceutical ingredient more difficult, in particular inaqueous and alcohol solvents, and therefore prevents, or at leastsignificantly reduces, the potential for abuse, while purportedlyallowing the pharmaceutical formulation to release the activepharmaceutical ingredient in the gastrointestinal tract upon ingestionto allow for the desired pharmacological effect. The drug formulation isin form of a tablet, comprising a salt of the abuse-susceptible activepharmaceutical ingredient, and an alkalizing agent for reducing thesolubility of the drug in no-acidic solutions.

The abuse problem that the present invention mitigates, is based onillicitly obtaining the abuse-susceptible active pharmaceuticalingredient from a capsule that comprises a fill which in turn comprisesthe abuse-susceptible active pharmaceutical ingredient.

Drug users are able to recover the fill and/or treat the fill to obtainthe active pharmaceutical ingredient therefrom. Such treatment includessolubilizing the fill with a small amount water, such as about 5 mL ofwater per 1 capsule. This mixture is then heated, optionally boiled, andfiltered through a filter, such as a cigarette filter, into a hypodermicsyringe. Such a syringe may be an insulin syringe equipped with aneedle. The syringes that are used for insulin injections typicallycomprise 20 to 31 gauge needles. Typically, due to viscosity challenges,the illicit drug user will select a relatively thicker gauge needles,such as a 20 gauge needle (about 0.91 mm outer diameter, 0.60 mm innerdiameter).

SUMMARY OF THE INVENTION

The present invention is directed to the development of an immediaterelease capsule formulation or an extended release capsule formulation.More specifically, the invention is directed to an immediate releasecapsule formulation, which mitigates the abuse of abuse-susceptibleactive pharmaceutical ingredients by direct intravenous injection.

One of the aspects of the present invention is to provide for a capsulecomprising a tamper resistant fill formulation which when mixed withwater and heated, results in a turbid, bubbling mixture that is notinjectable with a standard insulin syringe.

There are several different characteristics that may make the fillformulation abuse resistant. One characteristic that makes the fillformulation abuse resistant is that the viscosity increases upon heatingor boiling of the formulation in water. The viscosity of the mixture isincreased to such a level that it is difficult or impossible to fill theinsulin syringe with the mixture. Under one embodiment of the invention,the viscosity of the heated mixture increases to a level that it may notbe deliverable even through needles with the largest diameters commonlyused in delivery of insulin.

The second characteristic that makes a fill formulation abuse resistantis that upon heating or boiling the mixture of the fill with water,bubbles occur in the mixture. The presence of such bubbles makes it moredifficult to draw the mixture into the syringe. The bubbles also have adeterrent effect in that intravenous drug users tend to avoidintroduction of air bubbles into their bloodstream due to their fear ofair embolism.

Although there are many combinations of the fill components that maywork well to deliver the active pharmaceutical ingredient, it wassurprising that only certain combinations of the components result inparenteral abuse resistant fill formulations.

Generally, the present invention is directed to a parenteral abuseresistant liquid suitable for encapsulation in a capsule.

In the first aspect of the present invention, the parenteral abuseresistant liquid suitable for encapsulation in a capsule comprises: (a)an abuse-susceptible active pharmaceutical ingredient selected from thegroup consisting of opiates, opioids, tranquilizers, stimulants andnarcotics; (b) a viscosity enhancer or an ion exchange resin; and

(c) a surfactant; such that a mixture of about 250 to about 1000milligrams of the abuse resistant liquid with 5 milliliters of water atthe mixture's boiling point forms a viscous phase wherein about 33% orless of the pharmaceutically active ingredient can be recovered from theviscous phase drawn up into a 25 millimeter needle having an innerdiameter of 0.60 millimeters or which cannot pass through a 25millimeter needle having an inner diameter of 0.60 millimeters. In thesecond aspect of the present invention, the surfactant is aphosphatidylcholine concentrate.

In the third aspect of the present invention, the parenteral abuseresistant liquid comprises the liquid of the first aspect and (d) astabilizer. In the fourth aspect, the stabilizer is one of a colloidalanhydrous silica, a hard fat and a glycerol ester of long chain fattyacid. In the fifth aspect, the stabilizer is a colloidal anhydroussilica.

In the sixth aspect of the present invention, the parenteral abuseresistant liquid comprises the liquid of the fifth aspect and ahydrophilic carrier. In the seventh aspect, the hydrophilic carrier isone of macrogol 400, macrogol 600, macrogol 1500, propylene glycol,glycerol and water.

In the eighth aspect of the present invention, the parenteral abuseresistant liquid comprises the liquid of the third aspect and astabilizer selected from hard fat or a glycerol ester of long chainfatty acids. In the ninth aspect, the parenteral abuse resistant liquidcomprises the liquid of the third aspect, and (e) a lipophilic carrier.In the tenth aspect of the present invention, the lipophilic carrier isone of medium chain triglycerides, medium chain partial glycerides, anda vegetable oil.

In the eleventh aspect of the present invention, the parenteral abuseresistant liquid suitable for encapsulation in a capsule comprises: (a)an abuse-susceptible active pharmaceutical ingredient selected from thegroup consisting of opiates, opioids, tranquilizers, stimulants andnarcotics; (b) a gum selected from the group consisting of acacia,pectin, agar, tragacanth, guar gum, xanthan gum, locust bean gum, taragum, karaya, gellan gum, welan gum, and rhamsan gum; and (c) asurfactant; such that a mixture of about 250 to about 1000 milligrams ofthe abuse resistant liquid with 5 milliliters of water at the mixture'sboiling point forms a viscous phase wherein about 33% or less of thepharmaceutically active ingredient can be recovered from the viscousphase drawn up into a 25 millimeter needle having an inner diameter of0.60 millimeters or which cannot pass through a 25 millimeter needlehaving an inner diameter of 0.60 millimeters. In the twelfth aspect ofthe present invention, the gum is xanthan gum.

In the thirteenth aspect of the present invention, the parenteral abuseresistant liquid suitable for encapsulation in a capsule comprises: (a)an abuse-susceptible active pharmaceutical ingredient selected from thegroup consisting of opiates, opioids, tranquilizers, stimulants andnarcotics; (b) an ion exchange resin selected from the group consistingof polacrilex resin, sodium polystyrene sulfonate, potassiumpolyacrilin, and colestyramine resin; and (c) a surfactant; such that amixture of about 250 to about 1000 milligrams of the abuse resistantliquid with 5 milliliters of water at the mixture's boiling point formsa viscous phase wherein about 33% or less of the pharmaceutically activeingredient can be recovered from the viscous phase drawn up into a 25millimeter needle having an inner diameter of 0.60 millimeters or whichcannot pass through a 25 millimeter needle having an inner diameter of0.60 millimeters.

In the fourteenth aspect of the present invention, the parenteral abuseresistant liquid suitable for encapsulation in a capsule comprises: (a)an abuse-susceptible active pharmaceutical ingredient selected from thegroup consisting of opiates, opioids, tranquilizers, stimulants andnarcotics; (b) a viscosity enhancer or an ion exchange resin; and

(c) a polysorbate surfactant; such that a mixture of about 250 to about1000 milligrams of the abuse resistant liquid with 5 milliliters ofwater at the mixture's boiling point forms a viscous wherein about 33%or less of the pharmaceutically active ingredient can be recovered fromthe viscous phase drawn up into a 25 millimeter needle having an innerdiameter of 0.60 millimeters or which cannot pass through a 25millimeter needle having an inner diameter of 0.60 millimeters. In thefifteenth aspect, the parenteral abuse resistant liquid comprises apolysorbate surfactant selected from polysorbate 80, polysorbate 20,polyoxyethylene (20) sorbitane monolaurate, polyoxyethylene (20)sorbitane monopalmitate, polyoxyethylene (20) sorbitane monostearate,and polyoxyethylene (20) sorbitane monooleate.

In the sixteenth aspect of the present invention, the parenteral abuseresistant liquid suitable for encapsulation in a capsule comprises: (a)an abuse-susceptible active pharmaceutical ingredient selected from thegroup consisting of opiates, opioids, tranquilizers, stimulants andnarcotics; (b) a viscosity enhancer or an ion exchange resin; and

(c) a surfactant selected from the group consisting of macrogolglycerolricinoleate, sorbitol monolaurate, macrogolglycerol hydroxystearate andcaprylocaproylmacrogol-8-glycerides; such that a mixture of about 250 toabout 1000 milligrams of the abuse resistant liquid with 5 millilitersof water at the mixture's boiling point forms a viscous wherein about33% or less of the pharmaceutically active ingredient can be recoveredfrom the viscous phase drawn up into a 25 millimeter needle having aninner diameter of 0.60 millimeters or which cannot pass through a 25millimeter needle having an inner diameter of 0.60 millimeters.

In the seventeenth aspect of the present invention, the parenteral abuseresistant liquid suitable for encapsulation in a capsule comprises: (a)an abuse-susceptible active pharmaceutical ingredient selected from thegroup consisting of opiates, opioids, tranquilizers, stimulants andnarcotics; (b) a viscosity enhancer or an ion exchange resin;

(c) a surfactant; and (d) a carrier; such that a mixture of about 250 toabout 1000 milligrams of the abuse resistant liquid with 5 millilitersof water at the mixture's boiling point forms a viscous phase whereinabout 33% or less of the pharmaceutically active ingredient can berecovered from the viscous phase drawn up into a 25 millimeter needlehaving an inner diameter of 0.60 millimeters or which cannot passthrough a 25 millimeter needle having an inner diameter of 0.60millimeters.

In the eighteenth aspect of the present invention, the carrier isselected from glycerol distearate, glycerol dibehenate, medium chaintriglycerides, macrogol 400, macrogol 600, propyleneglycol, corn oil,corn oil monoglyceride, corn oil diglyceride, soybean oil, sesame oil,safflower oil, sunflower oil, ethanol, phospholipid concentrate, andmedium chain partial glycerides.

In the nineteenth aspect of the present invention, the parenteral abuseresistant liquid suitable for encapsulation in a capsule comprises: (a)an abuse-susceptible active pharmaceutical ingredient selected from thegroup consisting of opiates, opioids, tranquilizers, stimulants andnarcotics; (b) a viscosity enhancer or an ion exchange resin; and

(c) macrogol, caprylocaproylmacrogol-8 glycerides, water and glycerol;such that a mixture of about 250 to about 1000 milligrams of the abuseresistant liquid with 5 milliliters of water at the mixture's boilingpoint forms a viscous phase wherein about 33% or less of thepharmaceutically active ingredient can be recovered from the viscousphase drawn up into a 25 millimeter needle having an inner diameter of0.60 millimeters or which cannot pass through a 25 millimeter needlehaving an inner diameter of 0.60 millimeters.

In the twentieth aspect of the present invention, the parenteral abuseresistant liquid suitable for encapsulation in a capsule comprises: (a)an abuse-susceptible active pharmaceutical ingredient selected from thegroup consisting of opiates, opioids, tranquilizers, stimulants andnarcotics; (b) a viscosity enhancer or an ion exchange resin; and

(c) phosphatidylcholine, propylene glycol and caprylocaproyl macrogol-8glycerides; such that a mixture of about 250 to about 1000 milligrams ofthe abuse resistant liquid with 5 milliliters of water at the mixture'sboiling point forms a viscous phase wherein about 33% or less of thepharmaceutically active ingredient can be recovered from the viscousphase drawn up into a 25 millimeter needle having an inner diameter of0.60 millimeters or which cannot pass through a 25 millimeter needlehaving an inner diameter of 0.60 millimeters.

In the twenty-first aspect of the present invention, the parenteralabuse resistant liquid suitable for encapsulation in a capsulecomprises: (a) an abuse-susceptible active pharmaceutical ingredientselected from the group consisting of opiates, opioids, tranquilizers,stimulants and narcotics; (b) 2 to 20% ion exchange resin or 0.2 to 0.5%xanthan gum; (c) 40 to 60 wt % Macrogol 600, 3 to 6% glycerol, and 0.5to 10% water; and 15 to 25 wt % caprylocaproylmacrogol-8 glycerides; and(d) 3 to 10% colloidal anhydrous silica; wherein the weight percentagesare calculated with respect to the total weight of the parenteral abuseresistant liquid; and such that a mixture of about 250 to about 1000milligrams of the abuse resistant liquid with 5 milliliters of water atthe mixture's boiling point forms a viscous phase wherein about 33% orless of the pharmaceutically active ingredient can be recovered from theviscous phase drawn up into a 25 millimeter needle having an innerdiameter of 0.60 millimeters or which cannot pass through a 25millimeter needle having an inner diameter of 0.60 millimeters.

In the twenty-second aspect of the present invention, the parenteralabuse resistant liquid suitable for encapsulation in a capsulecomprises: (a) an abuse-susceptible active pharmaceutical ingredientselected from the group consisting of opiates, opioids, tranquilizers,stimulants and narcotics; (b) 2 to 5% xanthan gum; (c) 4 to 20% glycerolstearate or glycerol dibehenate; 10 to 70% medium chain triglycerides; 4to 50% polysorbate 80; 4 to 15% sorbitol monolaurate; and 3 to 10%macrogolglycerol ricinoleate or macrogolglycerol hydroxystearate; and(d) a stabilizer; 40 to 70% hard fat; and 1 to 5% colloidal anhydroussilica; wherein the weight percentages are calculated with respect tothe total weight of the parenteral abuse resistant liquid; and such thata mixture of about 250 to about 1000 milligrams of the abuse resistantliquid with 5 milliliters of water at the mixture's boiling point formsa viscous phase wherein about 33% or less of the pharmaceutically activeingredient can be recovered from the viscous phase drawn up into a 25millimeter needle having an inner diameter of 0.60 millimeters or whichcannot pass through a 25 millimeter needle having an inner diameter of0.60 millimeters.

In the twenty-third aspect of the present invention, the parenteralabuse resistant liquid suitable for encapsulation in a capsulecomprises: (a) an abuse-susceptible active pharmaceutical ingredientselected from the group consisting of opiates, opioids, tranquilizers,stimulants and narcotics; (b) 0.2 to 5% xanthan gum; (c) 50 to 80%phosphatidylcholine concentrate; 15 to 15% caprylocaproylmacrogol 8glycerides; 5 to 10% polysorbate 80; and 4 to 10% water; and (d) 1 to10% colloidal anhydrous silica;

wherein the weight percentages are calculated with respect to the totalweight of the parenteral abuse resistant liquid; and such that a mixtureof about 250 to about 1000 milligrams of the abuse resistant liquid with5 milliliters of water at the mixture's boiling point forms a viscousphase wherein about 33% or less of the pharmaceutically activeingredient can be recovered from the viscous phase drawn up into a 25millimeter needle having an inner diameter of 0.60 millimeters or whichcannot pass through a 25 millimeter needle having an inner diameter of0.60 millimeters.

In the twenty-fourth aspect of the present invention, the parenteralabuse resistant liquid suitable for encapsulation in a capsulecomprises: (a) an abuse-susceptible active pharmaceutical ingredientselected from the group consisting ofN-{1-[2-(4-ethyl-5-oxo-2-tetrazolin-1-yl)ethyl]-4-methoxymethyl-4-piperidyl}propionanilide;alfentanil; 5,5-diallylbarbituric acid; allobarbital; allylprodine;alphaprodine;8-chloro-1-methyl-6-phenyl-4H-[1,2,4]triazolo[4,3-a][1,4]-benzodiazepine;alprazolam; 2-diethylaminopropiophenone; amfepramone,(±)-αmethylphenethylamine; amphetamine;2-(α-methylphenethylamino)-2-phenylacetonitrile; amphetaminil;5-ethyl-5-isopentylbarbituric acid; amobarbital; anileridine;apocodeine; 5,5-diethylbarbituric acid; barbital; benzylmorphine;bezitramide; 7-bromo-5-(2-pyridyl)-1H-1,4-benzodiazepine-2(3H)-one;bromazepam;2-bromo-4-(2-chlorophenyl)-9-methyl-1-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine;brotizolam,17-cyclopropylmethyl-4,5a-epoxy-7a[(S)-1-hydroxy-1,2,2-trimethyl-propyl]-6-methoxy-6,14-endo-ethanomorphinan-3-ol;buprenorphine; 5-butyl-5-ethylbarbituric acid; butobarbital;butorphanol;(7-chloro-1,3-dihydro-1-methyl-2-oxo-5-phenyl-2H-1,4-benzodiazepin-3-yl)dimethylcarbamate;camazepam; (1S,2S)-2-amino-1-phenyl-1-propanol; cathine;d-norpseudoephedrine;7-chloro-N-methyl-5-phenyl-3H-1,4-benzodiazepin-2-yl-amine 4-oxide;chlordiazepoxide,7-chloro-1-methyl-5-phenyl-1H-1,5-benzodiazepine-2,4(3H,5H)-dione;clobazam, 5-(2-chlorophenyl)-7-nitro-1H-1,4-benzodiazepin-2(3H)-one;clonazepam; clonitazene;7-chloro-2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzodiazepine-3-carboxylicacid; clorazepate;5-(2-chlorophenyl)-7-ethyl-1-methyl-1H-thieno[2,3-e][1,4]diazepin-2(3H)-one;clotiazepam;10-chloro-11b-(2-chlorophenyl)-2,3,7,11b-tetrahydrooxazolo[3,2-d][1,4]benzodiazepin-6(5H)-one;cloxazolam; (−)-methyl-[3β-benzo yloxy-2β(1αH,5αH)-tropane carboxylate];cocaine;(5α,6α)-7,8-didehydro-4,5-epoxy-3-methoxy-17-methylmorphinan-6-ol;4,5α-epoxy-3-methoxy-17-methyl-7-morphinen-6α-ol; codeine;5-(1-cyclohexenyl)-5-ethyl barbituric acid; cyclobarbital; cyclorphan;cyprenorphine;7-chloro-5-(2-chloropheny-1)-1H-1,4-benzodiazepin-2(3H)-one;delorazepam; desomorphine; dextromoramide;(+)-(1-benzyl-3-dimethylamino-2-methyl-1-phenylpropyl)propionate;dextropropoxyphene; dezocine; diampromide; diamorphone;7-chloro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2(3H)-on; diazepam;4,5α-epoxy-3-methoxy-17-methyl-6α-morphinanol; dihydrocodeine;4,5α-epoxy-17-methyl-3,6α-morphinandiol; dihydromorphine; dimenoxadol;dimephetamol; dimethylthiambutene; dioxaphetyl butyrate; dipipanone;(6aR,10aR)-6,6,9-trimethyl-3-pentyl-6a,7,8,10a-tetrahydro-6H-benzo[c]chromen-1-ol;dronabinol; eptazocine;8-chloro-6-phenyl-4H-[1,2,4]-triazolo[4,3-(a)][1,4]benzodiazepine;estazolam; ethoheptazine; ethylmethylthiambutene;ethyl[7-chloro-5-(2-fluorophenyl)-2,3-dihydro-2-oxo-1H-1,4-benzodiazepine-3-carboxylate];ethyl loflazepate; 4,5α-epoxy-3-ethoxy-17-methyl-7-morphinen-6α-ol;ethylmorphine; etonitazene;4,5α-epoxy-7α-(1-hydroxy-1-methylbutyl)-6-methoxy-17-methyl-6,14-endo-etheno-morphinan-3-ol;etorphine; N-ethyl-3-phenyl-8,9,10-trinorbornan-2-ylamine; fencamfamine;7-[2-(α-methylphenethylamino)ethyl]-theophylline; fenethylline;3-(α-methylphenethylamino)propionitrile; fenproporex;N-(1-phenethyl-4-piperidyl)propionanilide; fentanyl;7-chloro-5-(2-fluorophenyl)-1-methyl-1H-1,4-benzodiazepin-2(3H)-one;fludiazepam;5-(2-fluorophenyl)-1-methyl-7-nitro-1H-1,4-benzodiazepin-2(3H)-one;flunitrazepam;7-chloro-1-(2-diethylaminoethyl)-5-(2-fluorophenyl)-1H-1,4-benzodiazepin-2(3H)-one;flurazepam;7-chloro-5-phenyl-1-(2,2,2-trifluoroethyl)-1H-1,4-benzodiazepin-2(3H)-one;halazepam;10-bromo-11b-(2-fluorophenyl)-2,3,7,11b-tetrahydro[1,3]oxazolyl[3,2-d][1,4]benzodiazepin-6(5H)-one;haloxazolam; heroin; 4,5α-epoxy-3-methoxy-17-methyl-6-morphinanone;hydrocodone; 4,5α-epoxy-3-hydroxy-17-methyl-6-morphinanone;hydromorphone; hydroxypethidine; isomethadone; hydroxymethylmorphinan;11-chloro-8,12b-dihydro-2,8-dimethyl-12b-phenyl-4H-[1,3]oxazino[3,2d][1,4]benzodiazepine-4,7(6H)-dione;ketazolam; 1-[4-(3-hydroxyphenyl)-1-methyl-4-piperidyl]-1-propanone;ketobemidone; (3S,6S)-6-dimethylamino-4,4-diphenylheptan-3-yl acetate;levacetylmethadol; LAAM; (−)-6-dimethylamino-4,4-diphenol-3-heptanone;levomethadone; (417-methyl-3-morphinanol; levorphanol;levophenacylmorphane; lofentanil;6-(2-chlorophenyl)-2-(4-methyl-1-piperazinylmethylene)-8-nitro-2H-imidazo[1,2-a][1,4]-benzodiazepin-1(4H)-one;loprazolam;7-chloro-5-(2-chlorophenyl)-3-hydroxy-1H-1,4-benzodiazepin-2(3H)-one;lorazepam;7-chloro-5-(2-chlorophenyl)-3-hydroxy-1-methyl-1H-1,4-benzodiazepin-2(3H)-one;lormetazepam;5-(4-chlorophenyl)-2,5-dihydro-3H-imidazo[2,1a]isoindol-5-ol; mazindol;7-chloro-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepine; medazepam;N-(3-chloropropyl)-α-methylphenethylamine; mefenorex; meperidine;2-methyl-2-propyltrimethylene dicarbamate; meprobamate; meptazinol;metazocine; methylmorphine; N,α-dimethylphenethylamine; metamphetamine;(±)-6-dimethylamino-4,4-diphenol-3-heptanone; methadone;2-methyl-3-o-tolyl-4(3H)-quinazolinone; methaqualone;methyl[2-phenyl-2-(2-piperidyflacetate]; methylphenidate;5-ethyl-1-methyl-5-phenylbarbituric acid; methylphenobarbital;3,3-diethyl-5-methyl-2,4-piperidinedione; methyprylon; metopon;8-chloro-6-(2-fluorophenyl)-1-methyl-4H-imidazo[1,5-a][1,4]benzodiazepine;midazolam; 2-(benzhydrylsulfinyl)acetamide; modafinil;(5α,6α)-7,8-didehydro-4,5-epoxy-17-methyl-7-methylmorphinan-3,6-diol;morphine; myrophine;(±)-trans-3-(1,1-dimethylheptyl)-7,8,10,10α-tetrahydro-1-hydroxy-6,6-dimethyl-6H-dibenzo-[b,d]pyran-9(6αH)one;nabilone; nalbuphene; nalorphine; narceine; nicomorphine;1-methyl-7-nitro-5-phenyl-1H-1,4-benzodiazepin-2(3H)-one; nimetazepam;7-nitro-5-phenyl-1H-1,4-benzodiazepin-2(3H)-one; nitrazepam;7-chloro-5-phenyl-1H-1,4-benzodiazepin-2(-3H)-one; nordazepam;norlevorphanol; 6-dimethylamino-4,4-diphenyl-3-hexanone; normethadone;normorphine; norpipanone; opium;7-chloro-3-hydroxy-5-phenyl-1H-1,4-benzodiazepin-2(3H)-one; oxazepam;(cis-/trans-)-10-chloro-2,3,7,11b-tetrahydro-2-methyl-11b-phenyloxazolo[3,2-d][1,4]benzodiazepin-6-(5H)-one;oxazolam; 4,5α-epoxy-14-hydroxy-3-methoxy-17-methyl-6-morphinanone;oxycodone; oxymorphone; papaveretum; 2-imino-5-phenyl-4-oxazolidinone;pernoline;1,2,3,4,5,6-hexahydro-6,11-dimethyl-3-(3-methyl-2-butenyl)-2,6-methano-3-benzazocin-8-ol;pentazocine; 5-ethyl-5-(1-methylbutyl)-barbituric acid; pentobarbital;ethyl-(1-methyl-4-phenyl-4-piperidinecarboxylate); pethidine;phenadoxone; phenomorphane; phenazocine; phenoperidine; piminodine;pholcodeine; 3-methyl-2-phenylmorpholine; phenmetrazine;5-ethyl-5-phenylbarbituric acid; phenobarbital;α,α-dimethylphenethylamine; phentermine;(R)-3-[-1-hydroxy-2-(methylamino)ethyl]phenol; phenylephrine,7-chloro-5-phenyl-1-(2-propynyl)-1H-1,4-benzodiazepin-2(3H)-one;pinazepam; α-(2-piperidyl)benzhydryl alcohol; pipradrol;1′-(3-cyano-3,3-diphenylpropyl)[1,4′-bipiperidine]-4′-carboxamide;piritramide;7-chloro-1-(cyclopropylmethyl)-5-phenyl-1H-1,4-benzodiazepin-2(3H)-one;prazepam; profadol; proheptazine; promedol; properidine; propoxyphene;N-(1-methyl-2-piperidinoethyl)-N-(2-pyridyl)propionamide;methyl{3-[4-methoxycarbonyl-4-(N-phenylpropanamido)piperidino]propanoate};(S,S)-2-methylamino-1-phenylpropan-1-ol; pseudoephedrine, remifentanil;5-sec-butyl-5-ethylbarbituric acid; secbutabarbital;5-allyl-5-(1-methylbutyl)-barbituric acid; secobarbital;N-{4-methoxymethyl-1-[2-(2-thienyl)ethyl]-4-piperidyl}propionanilide;sufentanil;7-chloro-2-hydroxymethyl-5-phenyl-1H-1,4-benzodiazepin-2(3H)-one;temazepam;7-chloro-5-(1-cyclohexenyl)-1-methyl-1H-1,4-benzodiazepin-2(3H)-one;tetrazepam; ethyl(2-dimethylamino-1-phenyl-3-cyclohexene-1-carboxylate;cis-/trans-tilidine; tramadol;8-chloro-6-(2-chlorophenyl)-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine;triazolam; 5-(1-methylbutyl)-5-vinylbarbituric acid; vinylbital;(1R*,2R*)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)phenol;(1R,2R,4S)-2-(dimethylamino)methyl-4-(p-fluorobenzyloxy)-1-(m-methoxyphenyl)cyclohexanol;a prodrug thereof; a pharmaceutically acceptable salt thereof; an adductthereof; and a solvate thereof; (b) a viscosity enhancer or an ionexchange resin; and (c) a surfactant; such that a mixture of about 250to about 1000 milligrams of the abuse resistant liquid with 5milliliters of water at the mixture's boiling point forms a viscousphase wherein about 33% or less of the pharmaceutically activeingredient can be recovered from the viscous phase drawn up into a 25millimeter needle having an inner diameter of 0.60 millimeters or whichcannot pass through a 25 millimeter needle having an inner diameter of0.60 millimeters.

In the twenty-fifth aspect of the present invention, the parenteralabuse resistant liquid suitable for encapsulation in a capsulecomprises: (a) an abuse-susceptible active pharmaceutical ingredientselected from the group consisting of codeine, tramadol, anileridine,prodine, pethidine, hydrocodone, morphine, oxycodone, methadone,diamorphine, hydromorphone, oxymorphone, 7-hydroxymitragynine,buprenorphine, fentanyl, sufentanil, levorphanol, meperidine,dihydrocodeine, dihydromorphine, morphine, hydromorphone, oxymorphone,tilidine, a prodrug thereof, a pharmaceutically acceptable salt thereof,and a solvate thereof; (b) a viscosity enhancer or an ion exchangeresin; and

(c) a surfactant; such that a mixture of about 250 to about 1000milligrams of the abuse resistant liquid with 5 milliliters of water atthe mixture's boiling point forms a viscous wherein about 33% or less ofthe pharmaceutically active ingredient can be recovered from the viscousphase drawn up into a 25 millimeter needle having an inner diameter of0.60 millimeters or which cannot pass through a 25 millimeter needlehaving an inner diameter of 0.60 millimeters.

In the twenty-sixth aspect of the present invention, the parenteralabuse resistant liquid suitable for encapsulation in a capsulecomprises: (a) an abuse-susceptible active pharmaceutical ingredientselected from the group consisting of opiates, opioids, tranquilizers,stimulants and narcotics; (b) a viscosity enhancer or an ion exchangeresin; and

(c) a surfactant; such that a mixture of about 250 to about 1000milligrams of the abuse resistant liquid with 5 milliliters of water atthe mixture's boiling point forms a viscous phase wherein about 33% orless of the pharmaceutically active ingredient can be recovered from theviscous phase drawn up into a 25 millimeter needle having an innerdiameter of 0.60 millimeters or which cannot pass through a 25millimeter needle having an inner diameter of 0.60 millimeters; and isresistant to alcohol dose dumping.

In the twenty-seventh aspect of the present invention, the parenteralabuse resistant liquid suitable for encapsulation in a capsulecomprises: (a) an abuse-susceptible active pharmaceutical ingredientselected from the group consisting of opiates, opioids, tranquilizers,stimulants and narcotics; (b) a viscosity enhancer or an ion exchangeresin; and

(c) a surfactant; such that a mixture of about 250 to about 1000milligrams of the abuse resistant liquid with 5 milliliters of water atthe mixture's boiling point forms a viscous phase wherein about 33% orless of the pharmaceutically active ingredient can be recovered from theviscous phase drawn up into a 25 millimeter needle having an innerdiameter of 0.60 millimeters or which cannot pass through a 25millimeter needle having an inner diameter of 0.60 millimeters; and isresistant to solvent, acidic or aqueous extraction.

Further, the present invention is directed to a parenteral abuseresistant capsule comprising the abuse resistant liquid in a formsuitable for encapsulation in a capsule.

In the twenty-eighth aspect of the present invention, the parenteralabuse resistant capsule comprises: (1) a fill including: (a) anabuse-susceptible active pharmaceutical ingredient selected from thegroup consisting of opiates, opioids, tranquilizers, stimulants andnarcotics; (b) a viscosity enhancer or an ion exchange resin; and (c) asurfactant; such that a mixture of about 250 to about 1000 milligrams ofthe abuse resistant liquid with 5 milliliters of water at the mixture'sboiling point forms a viscous phase wherein about 33% or less of thepharmaceutically active ingredient can be recovered from the viscousphase drawn up into a 25 millimeter needle having an inner diameter of0.60 millimeters or which cannot pass through a 25 millimeter needlehaving an inner diameter of 0.60 millimeters; and (2) a shell.

In the twenty-ninth aspect of the present invention, the parenteralabuse resistant capsule comprises: (1) a fill including: (a) anabuse-susceptible active pharmaceutical ingredient selected from thegroup consisting of opiates, opioids, tranquilizers, stimulants andnarcotics; (b) an ion exchange resin; and (c) a surfactant; such that amixture of about 250 to about 1000 milligrams of the abuse resistantliquid with 5 milliliters of water at the mixture's boiling point formsa viscous phase wherein about 33% or less of the pharmaceutically activeingredient can be recovered from the viscous phase drawn up into a 25millimeter needle having an inner diameter of 0.60 millimeters or whichcannot pass through a 25 millimeter needle having an inner diameter of0.60 millimeters; and (2) a shell; wherein the ion exchange resincreates a drug-ion exchange complex that dissociates within 30 minutesafter entry into the gastrointestinal tract.

In the thirtieth aspect of the present invention, the parenteral abuseresistant capsule comprises: (1) a fill including: (a) anabuse-susceptible active pharmaceutical ingredient selected from thegroup consisting of opiates, opioids, tranquilizers, stimulants andnarcotics; (b) a viscosity enhancer or an ion exchange resin; and (c) asurfactant; such that a mixture of about 250 to about 1000 milligrams ofthe abuse resistant liquid with 5 milliliters of water at the mixture'sboiling point forms a viscous phase wherein about 33% or less of thepharmaceutically active ingredient can be recovered from the viscousphase drawn up into a 25 millimeter needle having an inner diameter of0.60 millimeters or which cannot pass through a 25 millimeter needlehaving an inner diameter of 0.60 millimeters; and (2) a shell; whereinthe capsule releases more than 80% of the active pharmaceuticalingredient within the gastrointestinal tract within 30 minutes ofadministration.

In the thirty-first aspect of the present invention, the parenteralabuse resistant capsule comprises: (1) a fill including: (a) anabuse-susceptible active pharmaceutical ingredient selected from thegroup consisting of opiates, opioids, tranquilizers, stimulants andnarcotics; (b) a viscosity enhancer or an ion exchange resin; and (c) asurfactant; such that a mixture of about 250 to about 1000 milligrams ofthe abuse resistant liquid with 5 milliliters of water at the mixture'sboiling point forms a viscous phase wherein about 33% or less of thepharmaceutically active ingredient can be recovered from the viscousphase drawn up into a 25 millimeter needle having an inner diameter of0.60 millimeters or which cannot pass through a 25 millimeter needlehaving an inner diameter of 0.60 millimeters; and (2) a shell; and thecapsule provides extended release.

In the thirty-second aspect of the present invention, the parenteralabuse resistant capsule comprises: (1) a fill including: (a) anabuse-susceptible active pharmaceutical ingredient selected from thegroup consisting of opiates, opioids, tranquilizers, stimulants andnarcotics; (b) a viscosity enhancer or an ion exchange resin; and (c) asurfactant; such that a mixture of about 250 to about 1000 milligrams ofthe abuse resistant liquid with 5 milliliters of water at the mixture'sboiling point forms a viscous wherein about 33% or less of thepharmaceutically active ingredient can be recovered from the viscousphase drawn up into a 25 millimeter needle having an inner diameter of0.60 millimeters or which cannot pass through a 25 millimeter needlehaving an inner diameter of 0.60 millimeters; and (2) a shell; whereinthe capsule is a soft capsule or a hard capsule.

DETAILED DESCRIPTION

The present invention is directed to the development of an immediaterelease capsule formulation. More specifically, the invention isdirected to an immediate release capsule formulation, which mitigatesthe abuse of abuse-susceptible active pharmaceutical ingredients bydirect intravenous injection.

The present invention is also directed to the development of an extendedrelease capsule formulation. More specifically, the invention isdirected to an extended release capsule formulation, which mitigates theabuse of abuse-susceptible active pharmaceutical ingredients by directintravenous injection.

The abuse problem that the present invention mitigates is the illicitisolation of the abuse-susceptible active pharmaceutical ingredient froma capsule fill. The concern is that the user can recover the fillcomposition and solubilize the fill with a small amount water, such asabout 5 mL of water per 1 capsule. This mixture may then be heated,optionally boiled, and filtered through a filter, such as a cigarettefilter, into a hypodermic syringe. Such a syringe may be an insulinsyringe equipped with a needle. The syringes that are used for insulininjections typically comprise 20 to 31 gauge needles. Typically, due tothe viscosity of the material, the illicit drug user will selectrelatively thicker gauge needles, such as a 20 gauge needle (about 0.91mm outer diameter, 0.60 mm inner diameter). In the alternative, aplurality of capsules containing the fill comprising the activepharmaceutical ingredient is exposed to hot or boiling water tosolubilize the capsule shell to obtain the active pharmaceuticalingredient, which may be further purified.

For illustrative purposes, the principles of the present invention aredescribed by referencing various exemplary embodiments. Although certainembodiments of the invention are specifically described herein, one ofordinary skill in the art will readily recognize that the sameprinciples are equally applicable to, and can be employed in othersystems and methods. Before explaining the disclosed embodiments of thepresent invention in detail, it is to be understood that the inventionis not limited in its application to the details of any particularembodiment shown. Additionally, the terminology used herein is for thepurpose of description and not of limitation. Furthermore, althoughcertain methods are described with reference to steps that are presentedherein in a certain order, in many instances, these steps may beperformed in any order as may be appreciated by one skilled in the art;the novel method is therefore not limited to the particular arrangementof steps disclosed herein.

As used herein and in the appended claims, the singular forms “a”, “an”,and “the” include plural references unless the context clearly dictatesotherwise. Furthermore, the terms “a” (or “an”), “one or more” and “atleast one” can be used interchangeably herein. The terms “comprising”,“including”, “having” and “constructed from” can also be usedinterchangeably.

One of the aspects of the present invention is to provide for an abuseresistant liquid for encapsulation in a capsule which when mixed withwater and heated, results in a turbid, bubbling mixture that is notinjectable with a standard insulin syringe.

Another aspect of the present invention is to provide for a capsulecomprising a tamper resistant fill formulation which when mixed withwater and heated, results in a turbid, bubbling mixture that is notinjectable with a standard insulin syringe.

There are several different characteristics that may make the fillformulation abuse resistant. One characteristic that makes the fillformulation abuse resistant is that the viscosity increases upon heatingor boiling of the formulation in water. In this embodiment, uponexposure to water, the viscosity of the mixture increases to such alevel that it is difficult or impossible to fill the insulin syringewith the mixture. In one embodiment, the viscosity of the heated mixtureincreases to the level that it may not be deliverable even throughneedles with the largest diameters commonly used in delivery of insulin.

A second characteristic that makes a fill formulation abuse resistant isthat upon heating or boiling the mixture of the fill with water, bubblesoccur in the mixture. The presence of such bubbles makes it moredifficult to draw the mixture into the syringe. The bubbles also have adeterrent effect in that intravenous drug users tend to avoidintroduction of air bubbles into their bloodstream due to their fear ofan air embolism.

Another aspect of the present invention is an abuse resistant liquidsuitable for encapsulation in a capsule, which when mixed with water andheated, results in a mixture which when filtered to provide a liquidextract, the liquid extract comprises less than 33% of the dosage, and acapsule comprising such abuse resistant fill formulation.

Yet another aspect of the present invention is an abuse resistant liquidsuitable for encapsulation in a capsule, wherein the liquid comprises anion exchange resin that creates a drug ion exchange complex with theabuse-susceptible active pharmaceutical ingredient that dissociateswithin 30 minutes within the gastrointestinal tract, and a capsulecomprising such abuse resistant fill formulation.

A further aspect of the present invention is an immediate releasecapsule. Such a capsule releases more than 80% of the activepharmaceutical ingredient within the gastrointestinal tract within 30minutes of administration.

A still further aspect of the present invention is a controlled releasecapsule. An example of a controlled release capsule is an extendedrelease capsule.

Although there are many combinations of the fill components that maywork well to deliver the active pharmaceutical ingredient, it wassurprising that only certain combinations of components result inparenteral abuse resistant fill formulations.

The abuse resistant capsule of the present invention comprises the shelland the fill. The “fill”, as related to the present invention, is theliquid or semiliquid fluid that is encapsulated by the shell. Thecomposition of the fill is formulated so that the fill is tamperresistant.

The fill comprises the abuse-susceptible active pharmaceuticalingredient, and a blend of inactive ingredients. The blend may compriseone or more of a solvent, a surfactant, and a viscosity enhancer.Optionally, the blend may further comprise a plasticizer. Optionally,the blend may further comprise an ion exchange resin.

The abuse-susceptible active pharmaceutical ingredient as used in hereinis any pharmaceutically active ingredient that may be parenterallyabused.

Abuse-susceptible active pharmaceutical ingredients include opiates,opioids, tranquilizers, stimulants and narcotics as well as activepharmaceutical ingredients that are currently commonly abusedparenterally, and also any active pharmaceutical ingredient that has thepotential of being abused parenterally.

In one embodiment of the present invention, the abuse-susceptible activepharmaceutical ingredient is an opioid. The term “opioid” refers to apsychoactive compound that works by binding to opioid receptors. Opioidsare commonly used in the medical field for their analgesic effects.Examples of opioids include codeine, tramadol, anileridine, prodine,pethidine, hydrocodone, morphine, oxycodone, methadone, diamorphine,hydromorphone, oxymorphone, 7-hydroxymitragynine, buprenorphine,fentanyl, sufentanil, levorphanol, meperidine, tilidine, dihydrocodeine,and dihydromorphine.

Examples of the abuse-susceptible active pharmaceutical ingredientincludeN-{1-[2-(4-ethyl-5-oxo-2-tetrazolin-1-yl)ethyl]-4-methoxymethyl-4-piperidyl}propionanilide;alfentanil; 5,5-diallylbarbituric acid; allobarbital; allylprodine;alphaprodine;8-chloro-1-methyl-6-phenyl-4H-[1,2,4]triazolo[4,3-a][1,4]-benzodiazepine;alprazolam; 2-diethylaminopropiophenone; amfepramone,(±)-αmethylphenethylamine; amphetamine;2-(α-methylphenethylamino)-2-phenylacetonitrile; amphetaminil;5-ethyl-5-isopentylbarbituric acid; amobarbital; anileridine;apocodeine; 5,5-diethylbarbituric acid; barbital; benzylmorphine;bezitramide; 7-bromo-5-(2-pyridyl)-1H-1,4-benzodiazepine-2(3H)-one;bromazepam;2-bromo-4-(2-chlorophenyl)-9-methyl-1-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine;brotizolam,17-cyclopropylmethyl-4,5a-epoxy-7a[(S)-1-hydroxy-1,2,2-trimethyl-propyl]-6-methoxy-6,14-endo-ethanomorphinan-3-ol;buprenorphine; 5-butyl-5-ethylbarbituric acid; butobarbital;butorphanol;(7-chloro-1,3-dihydro-1-methyl-2-oxo-5-phenyl-2H-1,4-benzodiazepin-3-yl)dimethylcarbamate;camazepam; (1S,2S)-2-amino-1-phenyl-1-propanol; cathine;d-norpseudoephedrine;7-chloro-N-methyl-5-phenyl-3H-1,4-benzodiazepin-2-yl-amine 4-oxide;chlordiazepoxide,7-chloro-1-methyl-5-phenyl-1H-1,5-benzodiazepine-2,4(3H,5H)-dione;clobazam, 5-(2-chlorophenyl)-7-nitro-1H-1,4-benzodiazepin-2(3H)-one;clonazepam; clonitazene;7-chloro-2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzodiazepine-3-carboxylicacid; clorazepate;5-(2-chlorophenyl)-7-ethyl-1-methyl-1H-thieno[2,3-e][1,4]diazepin-2(3H)-one;clotiazepam;10-chloro-11b-(2-chlorophenyl)-2,3,7,11b-tetrahydrooxazolo[3,2-d][1,4]benzodiazepin-6(5H)-one;cloxazolam; (−)-methyl-[3β-benzoyloxy-2β(1αH,5αH)-tropane carboxylate];cocaine;(5α,6α)-7,8-didehydro-4,5-epoxy-3-methoxy-17-methylmorphinan-6-ol;4,5α-epoxy-3-methoxy-17-methyl-7-morphinen-6α-ol; codeine;5-(1-cyclohexenyl)-5-ethyl barbituric acid; cyclobarbital; cyclorphan;cyprenorphine;7-chloro-5-(2-chloropheny-1)-1H-1,4-benzodiazepin-2(3H)-one;delorazepam; desomorphine; dextromoramide;(+)-(1-benzyl-3-dimethylamino-2-methyl-1-phenylpropyl)propionate;dextropropoxyphene; dezocine; diampromide; diamorphone;7-chloro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2(3H)-on; diazepam;4,5α-epoxy-3-methoxy-17-methyl-6α-morphinanol; dihydrocodeine;4,5α-epoxy-17-methyl-3,6α-morphinandiol; dihydromorphine; dimenoxadol;dimephetamol; dimethylthiambutene; dioxaphetyl butyrate; dipipanone;(6aR,10aR)-6,6,9-trimethyl-3-pentyl-6a,7,8,10a-tetrahydro-6H-benzo[c]chromen-1-ol;dronabinol; eptazocine;8-chloro-6-phenyl-4H-[1,2,4]-triazolo[4,3-(a)][1,4]benzodiazepine;estazolam; ethoheptazine; ethylmethylthiambutene;ethyl[7-chloro-5-(2-fluorophenyl)-2,3-dihydro-2-oxo-1H-1,4-benzodiazepine-3-carboxylate];ethyl loflazepate; 4,5α-epoxy-3-ethoxy-17-methyl-7-morphinen-6α-ol;ethylmorphine; etonitazene;4,5α-epoxy-7α-(1-hydroxy-1-methylbutyl)-6-methoxy-17-methyl-6,14-endo-etheno-morphinan-3-ol;etorphine; N-ethyl-3-phenyl-8,9,10-trinorbornan-2-ylamine; fencamfamine;7-[2-(α-methylphenethylamino)ethyl]-theophylline; fenethylline;3-(α-methylphenethylamino)propionitrile; fenproporex;N-(1-phenethyl-4-piperidyl)propionanilide; fentanyl;7-chloro-5-(2-fluorophenyl)-1-methyl-1H-1,4-benzodiazepin-2(3H)-one;fludiazepam;5-(2-fluorophenyl)-1-methyl-7-nitro-1H-1,4-benzodiazepin-2(3H)-one;flunitrazepam;7-chloro-1-(2-diethylaminoethyl)-5-(2-fluorophenyl)-1H-1,4-benzodiazepin-2(3H)-one;flurazepam;7-chloro-5-phenyl-1-(2,2,2-trifluoroethyl)-1H-1,4-benzodiazepin-2(3H)-one;halazepam;10-bromo-11b-(2-fluorophenyl)-2,3,7,11b-tetrahydro[1,3]oxazolyl[3,2-d][1,4]benzodiazepin-6(5H)-one;haloxazolam; heroin; 4,5α-epoxy-3-methoxy-17-methyl-6-morphinanone;hydrocodone; 4,5α-epoxy-3-hydroxy-17-methyl-6-morphinanone;hydromorphone; hydroxypethidine; isomethadone; hydroxymethylmorphinan;11-chloro-8,12b-dihydro-2,8-dimethyl-12b-phenyl-4H-[1,3]oxazino[3,2d][1,4]benzodiazepine-4,7(6H)-dione;ketazolam; 1-[4-(3-hydroxyphenyl)-1-methyl-4-piperidyl]-1-propanone;ketobemidone; (3S,6S)-6-dimethylamino-4,4-diphenylheptan-3-yl acetate;levacetylmethadol; LAAM; (−)-6-dimethylamino-4,4-diphenol-3-heptanone;levomethadone; (−)-17-methyl-3-morphinanol; levorphanol;levophenacylmorphane; lofentanil;6-(2-chlorophenyl)-2-(4-methyl-1-piperazinylmethylene)-8-nitro-2H-imidazo[1,2-a][1,4]-benzodiazepin-1(4H)-one;loprazolam;7-chloro-5-(2-chlorophenyl)-3-hydroxy-1H-1,4-benzodiazepin-2(3H)-one;lorazepam;7-chloro-5-(2-chlorophenyl)-3-hydroxy-1-methyl-1H-1,4-benzodiazepin-2(3H)-one;lormetazepam;5-(4-chlorophenyl)-2,5-dihydro-3H-imidazo[2,1a]isoindol-5-ol; mazindol;7-chloro-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepine; medazepam;N-(3-chloropropyl)-α-methylphenethylamine; mefenorex; meperidine;2-methyl-2-propyltrimethylene dicarbamate; meprobamate; meptazinol;metazocine; methylmorphine; N,α-dimethylphenethylamine; metamphetamine;(±)-6-dimethylamino-4,4-diphenol-3-heptanone; methadone;2-methyl-3-o-tolyl-4(3H)-quinazolinone; methaqualone;methyl[2-phenyl-2-(2-piperidyl)acetate]; methylphenidate;5-ethyl-1-methyl-5-phenylbarbituric acid; methylphenobarbital;3,3-diethyl-5-methyl-2,4-piperidinedione; methyprylon; metopon;8-chloro-6-(2-fluorophenyl)-1-methyl-4H-imidazo[1,5-a][1,4]benzodiazepine;midazolam; 2-(benzhydrylsulfinyl)acetamide; modafinil;(5α,6α)-7,8-didehydro-4,5-epoxy-17-methyl-7-methylmorphinan-3,6-diol;morphine; myrophine;(±)-trans-3-(1,1-dimethylheptyl)-7,8,10,10α-tetrahydro-1-hydroxy-6,6-dimethyl-6H-dibenzo-[b,d]pyran-9(6αH)one;nabilone; nalbuphene; nalorphine; narceine; nicomorphine;1-methyl-7-nitro-5-phenyl-1H-1,4-benzodiazepin-2(3H)-one; nimetazepam;7-nitro-5-phenyl-1H-1,4-benzodiazepin-2(3H)-one; nitrazepam;7-chloro-5-phenyl-1H-1,4-benzodiazepin-2(-3H)-one; nordazepam;norlevorphanol; 6-dimethylamino-4,4-diphenyl-3-hexanone; normethadone;normorphine; norpipanone; opium;7-chloro-3-hydroxy-5-phenyl-1H-1,4-benzodiazepin-2(3H)-one; oxazepam;(cis-/trans-)-10-chloro-2,3,7,11b-tetrahydro-2-methyl-11b-phenyloxazolo[3,2-d][1,4]benzodiazepin-6-(5H)-one;oxazolam; 4,5α-epoxy-14-hydroxy-3-methoxy-17-methyl-6-morphinanone;oxycodone; oxymorphone; papaveretum; 2-imino-5-phenyl-4-oxazolidinone;pernoline;1,2,3,4,5,6-hexahydro-6,11-dimethyl-3-(3-methyl-2-butenyl)-2,6-methano-3-benzazocin-8-ol;pentazocine; 5-ethyl-5-(1-methylbutyl)-barbituric acid; pentobarbital;ethyl-(1-methyl-4-phenyl-4-piperidinecarboxylate); pethidine;phenadoxone; phenomorphane; phenazocine; phenoperidine; piminodine;pholcodeine; 3-methyl-2-phenylmorpholine; phenmetrazine;5-ethyl-5-phenylbarbituric acid; phenobarbital;α,α-dimethylphenethylamine; phentermine;(R)-3-[-1-hydroxy-2-(methylamino)ethyl]phenol; phenylephrine,7-chloro-5-phenyl-1-(2-propynyl)-1H-1,4-benzodiazepin-2(3H)-one;pinazepam; α-(2-piperidyl)benzhydryl alcohol; pipradrol;1′-(3-cyano-3,3-diphenylpropyl)[1,4′-bipiperidine]-4′-carboxamide;piritramide;7-chloro-1-(cyclopropylmethyl)-5-phenyl-1H-1,4-benzodiazepin-2(3H)-one;prazepam; profadol; proheptazine; promedol; properidine; propoxyphene;N-(1-methyl-2-piperidinoethyl)-N-(2-pyridyl)propionamide;methyl{3-[4-methoxycarbonyl-4-(N-phenylpropanamido)piperidino]propanoate};(S,S)-2-methylamino-1-phenylpropan-1-ol; pseudoephedrine, remifentanil;5-sec-butyl-5-ethylbarbituric acid; secbutabarbital;5-allyl-5-(1-methylbutyl)-barbituric acid; secobarbital;N-{4-methoxymethyl-1-[2-(2-thienyl)ethyl]-4-piperidyl}propionanilide;sufentanil;7-chloro-2-hydroxymethyl-5-phenyl-1H-1,4-benzodiazepin-2(3H)-one;temazepam;7-chloro-5-(1-cyclohexenyl)-1-methyl-1H-1,4-benzodiazepin-2(3H)-one;tetrazepam; ethyl(2-dimethylamino-1-phenyl-3-cyclohexene-1-carboxylate;cis-/trans-tilidine; tramadol;8-chloro-6-(2-chlorophenyl)-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine;triazolam; 5-(1-methylbutyl)-5-vinylbarbituric acid; vinylbital;(1R*,2R*)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)phenol;(1R,2R,4S)-2-(dimethylamino)methyl-4-(p-fluorobenzyloxy)-1-(m-methoxyphenyl)cyclohexanol.

In addition to the above compounds, abuse-susceptible activepharmaceutical ingredients also include a prodrug of any of thesecompounds. The term “prodrug” means a compound that is a metabolicprecursor to the active pharmaceutical ingredient. This precursor istransformed in vivo to provide the active pharmaceutical ingredientwhich has the desired therapeutic effect.

Abuse-susceptible active pharmaceutical ingredients also includepharmaceutically acceptable salts of any of the above-mentionedcompounds. The phrase “pharmaceutically acceptable salt” of a compoundmeans a salt that is pharmaceutically acceptable and that possesses thedesired pharmacological activity of the parent compound. Such saltsinclude, for example, acid addition salts, formed with inorganic acidssuch as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,phosphoric acid, and the like; or formed with organic acids such asacetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid,glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid,malic acid, maleic acid, fumaric acid, tartaric acid, citric acid,benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelicacid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonicacid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid,4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid,4-toluenesulfonic acid, camphorsulfonic acid,4-methylbicyclo[2.2.2]-oct-2-ene-1-carboxylic acid, glucoheptonic acid,3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid,lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoicacid, salicylic acid, stearic acid, muconic acid, and the like; andsalts formed when an acidic proton present in the parent compound eitheris replaced by a metal ion, e.g., an alkali metal ion, an alkaline earthion, or an aluminum ion; or coordinates with an organic base such asethanolamine, diethanolamine, triethanolamine, tromethamine,N-methylglucamine, and the like. Representative salts include thehydrobromide, hydrochloride, sulfate, bisulfate, nitrate, acetate,oxalate, valerate, oleate, palmitate, stearate, laurate, borate,benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate,succinate, tartrate, naphthylate mesylate, glucoheptonate, lactobionateand laurylsulphonate salts, and the like. These may include cationsbased on the alkali and alkaline earth metals, such as sodium, lithium,potassium, calcium, magnesium, and the like, as well as non-toxicammonium, tetramethylammonium, tetramethylammonium, methylamine,dimethylamine, trimethylamine, triethylamine, ethylamine, and the like.

The phrase “pharmaceutically acceptable” means that which is useful inpreparing a pharmaceutical composition that is generally safe,non-toxic, and is not biologically or otherwise undesirable and isacceptable for human pharmaceutical use.

Furthermore, in addition to the above compounds, abuse-susceptibleactive pharmaceutical ingredients also include solvates of any of theabove-mentioned compounds. The term “solvate” refers to an aggregatethat comprises one or more molecules of abuse-susceptible activepharmaceutical ingredient with one or more molecules of a solvent. Thesolvent may be water, in which case the solvate may be a hydrate.Alternatively, the solvent may be an organic solvent. In one embodiment,“solvate” refers to the abuse-susceptible active pharmaceuticalingredient in its state prior to dissolution. Alternatively, the solidparticles of a suspended abuse-susceptible active pharmaceuticalingredient may comprise a co-precipitated solvent.

The parenteral abuse resistant capsule of the present invention maycomprise a liquid blend as part of the fill. The liquid blend comprisesany pharmaceutically acceptable components so as to solubilize ormiscibilize the abuse-susceptible active pharmaceutical ingredient. Thecomponents of the liquid blend may be compounds useful to prepare apharmaceutical composition, generally safe, non-toxic and neitherbiologically nor otherwise undesirable, and includes compounds that areacceptable for veterinary use as well as human pharmaceutical use.

The phrase “liquid blend” means the fill of the capsule fill except forthe abuse-susceptible active pharmaceutical ingredient. The liquid blendcomprises selected pharmaceutically acceptable components such as asolvent, a surfactant, and a viscosity enhancer. The liquid blend mayalso comprise another active pharmaceutical ingredient that is not anabuse-susceptible active pharmaceutical ingredient.

One of the components of the liquid blend may be a solvent or a carrier.The fill may comprise more than one solvent. The solvent is anypharmaceutically acceptable solvent that solubilizes the activepharmaceutical ingredient and optionally other components of the liquidblend. The solvent can be hydrophilic, amphiphilic or lipophilic.Exemplary solvents include polyethylene glycol, propylene glycol, mediumchain triglycerides, corn oil mono- and diglycerides, refined soybeanoil, refined sesame oil, ethanol, phospholipid concentrates, poloxamersand medium chain partial glycerides.

Another component of the liquid blend of the present invention may be asurfactant. The liquid blend may comprise more than one surfactant.

Another optional component of the liquid blend of the present inventionis a viscosity enhancer, or a gelling agent.

The liquid blend of the present invention balances at least threedifferent properties: (1) solubilization of the active pharmaceutical;(2) abuse resistance; and (3) release profile. The release profile maybe either immediate or extended. Other additional considerations includelong term stability, and ease of processing.

In one embodiment of the present invention, the active pharmaceuticalingredient is dissolved or suspended in a lipophilic self-emulsifyingdrug delivery system that is not injectable with a standard insulinsyringe. The solubility of the abuse-susceptible active pharmaceuticalingredient must be sufficient to solubilize a therapeutically effectiveamount of the abuse-susceptible active pharmaceutical ingredient.Alternatively, the abuse-susceptible active pharmaceutical ingredientmay form a stable suspension.

The liquid blend of the present invention exhibits abuse resistance. Inone embodiment, the abuse resistant fill provides no more than 33% ofthe abuse-susceptible active pharmaceutical ingredient for parenteraldelivery, or no more than 25% of the abuse-susceptible activepharmaceutical ingredient for parenteral delivery, or no more than 15%of the abuse-susceptible active pharmaceutical ingredient for parenteraldelivery, or no more than 10% of the abuse-susceptible activepharmaceutical ingredient for parenteral delivery, or no more than 5% ofthe abuse-susceptible active pharmaceutical ingredient for parenteraldelivery or essentially none of the abuse-susceptible activepharmaceutical ingredient for parenteral delivery.

Parenteral abuse resistant capsule fill formulations that showacceptable solubility and that comprise colloidal anhydrous silica and agum also exhibit abuse resistant properties. Such formulations includesolvents such as medium chain triglycerides. Formulations that comprisemedium chain triglycerides, colloidal anhydrous silica, and xanthan gum,also include a polysorbate surfactant.

Other solvent and surfactant combinations in the liquid blend that showabuse resistant properties when colloidal anhydrous silica and xanthangum is present, include polyethylene glycol, and a surfactant selectedfrom the group consisting of polyoxyl 40 hydrogenated castor oil,polysorbate surfactant, caprylocaproyl macrogol-8 glyceride, andglycerol. Examples of polyethylene glycol include macrogol 400 andmacrogol 600.

Furthermore, it was found that a liquid blend comprising a phospholipidconcentrate and a polysorbate surfactant also exhibits acceptablesolubility and abuse resistance. The polysorbate surfactant may includepolyoxyethylene (20) sorbitanmonolaurate, polyoxyethylene (20) sorbitanmonopalmitate, polyoxyethylene (20) sorbitanmonostearate, and/orpolyoxyethylene (20) sorbitanmonooleate. Examples of phospholipidconcentrates include Phosal 50 PG, and Lipoid PPL 600.

Yet another combination of liquid blend components that exhibitsolubility and abuse resistance is a liquid blend comprisingpolyethylene glycol, caprylocaproyl macrogol-8 glycerides, glycerol, anda viscosity enhancer. The viscosity enhancer may be a mixture ofcolloidal anhydrous silica and a gum.

In one aspect of the present invention an abuse resistant liquidsuitable for encapsulation in a capsule, comprises: (a) anabuse-susceptible active pharmaceutical ingredient selected from thegroup consisting of opiates, opioids, tranquilizers, stimulants andnarcotics; (b) a viscosity enhancer or an ion exchange resin; and (c) asurfactant; such that a mixture of about 250 milligrams to about 1000milligrams of the abuse resistant liquid with 5 milliliters of water atthe mixture's boiling point forms a viscous phase from which less than33% of the active pharmaceutical ingredient is recovered by a 25millimeter needle having an inner diameter of 0.60 millimeters. Inparticular embodiments, mixtures of about 250 mg, about 500 mg, about750 mg or about 1000 mg of the abuse resistant liquid with 5 ml of waterat the mixture's boiling point form the viscous phase.

As discussed in the experimental section below, the 1000 mg mixture hasan excellent correlation to the tamper resistance characteristics of thecapsule of fill weight of about 900 to 950 milligrams. All liquidmixtures, which fulfilled the tamper resistance requirement also showedgood dispersability, at amounts of 250 mg and 1000 mg.

The term “parenteral” as used in the phrase “parenteral abuse resistantcapsule” means that the abuse-susceptible active pharmaceuticalingredient is introduced into the human body via a parenteral route. Theterm “parenteral” includes introduction of the abuse-susceptible activepharmaceutical ingredient into the body via injection. Such an injectionmay be intradermal, subcutaneous, transdermal, intravenous, orintramuscular.

The phrase “abuse resistant” when referring to the parenteral abuseresistant capsule, means that it is difficult for an average drug abuserto take the necessary steps to isolate the abuse-susceptible activepharmaceutical ingredient from the capsule to the level necessary tointroduce the abuse-susceptible active pharmaceutical ingredientparenterally. The degree of difficulty in obtaining theabuse-susceptible active pharmaceutical ingredient ranges fromimpossibility (0% of the abuse-susceptible active pharmaceuticalingredient is delivered parenterally) to challenging (33% of theabuse-susceptible active pharmaceutical ingredient is deliveredparenterally).

The parenteral abuse resistant liquid may comprise either a viscosityenhancer or an ion exchange resin.

The viscosity enhancer, also known as a gelling agent, is selected fromany pharmaceutically acceptable viscosity enhancers. The viscosityenhancer may comply with the pharmaceutical compendial standards aslisted below. The fill may comprise more than one viscosity enhancer.Exemplary viscosity enhancers include gums such as acacia, agar,tragacanth, guar gum, xanthan gum, locust bean gum, tara gum, karaya,gellan gum, welan gum, and rhamsan gum.

An alternative to the viscosity enhancer is an ion exchange resin.Although the ion exchange resins generally have thickening effects onthe liquid, not all ion exchange resins exhibit such a property.Examples of the ion exchange resin include polacrilex resin, sodiumpolystyrene sulfonate, potassium polyacrilin, and colestyramine resin.These exemplary ion exchange resins are commercially available asAmberlite® IRP64, Amberlite® IRP69, Amberlite® IRP88, and Duolite AP143/1093. (AMBERLITE and DUOLITE are registered trademarks of Rohm &Haas Company, its subsidiaries or their successors).

A third component of the parenteral abuse resistant liquid may be asurfactant. The parenteral abuse resistant liquid may comprise more thanone surfactant. The surfactant is selected from any pharmaceuticallyacceptable surfactants. The surfactant may comply with thepharmaceutical compendial standards as listed herein.

Exemplary surfactants include polysorbate 20, Tween® 20, polysorbate 80,Tween® 80, macrogolglycerol hydroxystearate, Cremophor® RH 40,macrogolglycerol ricinoleate, Cremophor® EL, glycerolmonooleate 40,Peceol™, macrogolglycerol linoleate, Labrafil M 2125 CS, propyleneglycol monolaurate FCC, Lauroglycol FCC, polyglycerol-6-dioleate,polyglycerol-3-dioleate, Plurol® Oleique, propylene glycolmonocaprylate, Capryol® 90, sorbitanmonolaurate, Span® 20,sorbitanmonooleate, Span® 80, Vitamin E-polyethylenglycol-succinate,caprylocaproyl macrogol-8 glycerides, Labrasol®,macrogol-32-glycerol-laurate, Gelucire 44/14,glycerylmonocaprate/caprylate, Capmul MCM.

In one embodiment, the parenteral abuse resistant liquid comprises apolysorbate surfactant. Examples of the polysorbate surfactant includepolysorbate 80, polysorbate 20, polyoxyethylene (20) sorbitanemonolaurate, polyoxyethylene (20) sorbitane monopalmitate,polyoxyethylene (20) sorbitane monostearate, and polyoxyethylene (20)sorbitane monooleate.

In another embodiment, the parenteral abuse resistant liquid comprises asurfactant selected from the group consisting of macrogolglycerolricinoleate, macrogolglycerol hydroxystearate andcaprylocaproylmacrogol-8-glycerides.

Polysorbate 20 also known as, or similar to, or related to,polyoxyethylene (20) sorbitan monolaurate or sorbitan monolaurate, thatis typically sold under brand names such as Alkest® TW 20 and Tween® 20.Polysorbate 20 is a mixture of partial esters of fatty acids, mainlylauric acid, with sorbitol and its anhydrides ethoxylated withapproximately 20 moles of ethylene oxide for each mole of sorbitol andsorbitol anhydrides. Polysorbate 20 is a polysorbate surfactant withstability and relatively low toxicity. CAS Number 9005-64-5.

Polysorbate 80, also known as, or similar to, or related to,polyethylene glycol sorbitan monooleate, is a common name forpolyoxyethylene (20) sorbitan monooleate, that is typically sold underbrand names such as Alkest TW 80 and Tween® 80. Polysorbate 80 is amixture of partial esters of fatty acids, mainly oleic acid, withsorbitol and its anhydrides ethoxylated with approximately 20 moles ofethylene oxide for each mole of sorbitol and sorbitol anhydrides.Polysorbate 80 is a nonionic surfactant and emulsifier derived frompolyethoxylated sorbitan and oleic acid. CAS Number 9005-65-6.

Macrogolglycerol hydroxystearate also known as, or similar to, orrelated to, PEG-40 castor oil, polyoxyl 40 hydrogenated castor oil, andis generally sold under brand names such as Cremophor® RH 40, orKolliphor® RH 40. Macrogolglycerol hydroxystearate contains mainlytrihydroxystearyl glycerol ethoxylated with 7 to 60 molecules ofethylene oxide (nominal value), with small amounts of macrogolhydroxystearate and of the corresponding free glycols. It results fromthe reaction of hydrogenated castor oil with ethylene oxide. CAS Number61788-85-0.

Macrogolglycerol ricinoleate, also known as, or similar to, or relatedto, as PEG-35 castor oil, polyoxyl 35 hydrogenated castor oil, orpolyoxyl-35 castor oil, and is generally sold under brand names such asKolliphor EL, and Cremophor EL. Macrogolglycerol ricinoleate containsmainly ricinoleyl glycerol ethoxylated with 30 to 50 molecules ofethylene oxide (nominal value), with small amounts of macrogolricinoleate and of the corresponding free glycols. It results from thereaction of castor oil with ethylene oxide. CAS Number 61791-12-6.

Glycerol monooleate 40, also known as, or similar to, or related to,1,3-dihydroxy-2-propanyl(9Z)-9-octadecenoate, 2-oleoylglycerol, Peceol™.Formula: CH₃(CH₂)₇CH═CH(CH₂)₇COO—CH₂CHOHCH₂OH, CAS Numbers 111-03-5 and3443-84-3.

Labrafil M 2125 CS, also known as, or similar to, or related to,linoleoyl macrogol-6 glycerides, linoleoyl polyoxyl-6 glycerides, cornoil PEG-6 esters, is a water dispersible surfactant composed ofwell-characterized PEG-esters and a glycerides fraction.

Propylene glycol monolaurate EP/NF, also known as, or similar to, orrelated to, Lauroglycol™ FCC, is a mixture of the propylene glycol mono-and di-esters of lauric acid. It is a water insoluble surfactant for usein self emulsifying systems to obtain a coarse dispersion, i.e.,emulsion (SEDDS) or a fine dispersion, i.e., microemulsion (SMEDDS). CASnumber 27194-74-7. Propylene glycol monolaurate, as used throughout thisdocument, may be a Type I propylene glycol monolaurate (comprising 45.0%to 70.0% of monoesters and 30.0% to 55.0% of diesters), or Type IIpropylene glycol monolaurate (comprising minimum 90.0% of monoesters andmaximum 10.0% of diesters).

Polyglycerol-6-dioleate, also known as, or similar to, or related to,homohexamer di[(9Z)-9-octadecenoate] 1,2,3-propanetriol, hexaglycerildioleate, is a diester of oleic acid and a glycerin polymer containingan average of 6 glycerin units. It is available, for example, fromGattefossé under the trademark Plurol Stearique WL 1009. CAS number76009-37-5.

Polyglyceryl-3-oleate, also known as, or similar to, or related to,polyglyceryl-3 dioleate, triglyceryl dioleate, polyglycerol oleate,polyglyceryl oleate, triglyceryl monooleate, is a diester of oleic acidand a glycerin polymer containing an average of 3 glycerin units,available from under the trademark Plurol® Oleique CC 497. CAS number9007-48-1.

Propylene glycol monocaprylate, also known as, or similar to, or relatedto, 1,2-propanediol monocaprylate, Capryol™ 90, and propylene glycolcaprylate, is a water insoluble surfactant for use in self emulsifyingsystems to obtain a coarse dispersion, i.e., emulsion (SEDDS) or a finedispersion, i.e., microemulsion (SMEDDS). CAS numbers 31565-12-5,132721-32-5.

Sorbitan monostearate, also known as, or similar to, or related to,octadecanoic acid[2-[(2R,3S,4R)-3,4-dihydroxy-2-tetrahydrofuranyl]-2-hydroxyethyl]ester,is an ester of sorbitan (a sorbitol derivative) and stearic acid and issometimes referred to as a synthetic wax. Sorbitan monostearate isusually obtained by partial esterification of sorbitol and its mono- anddi-anhydrides with stearic acid 50, or stearic acid 70. It is frequentlyused as an emulsifier to keep water and oils mixed. CAS number:1338-41-6.

Sorbitan monolaurate, also known as, or similar to, or related to,sorbitan monododecanoate, dodecanoic acid[2-[(2R,3R,4S)-3,4-dihydroxy-2-tetrahydrofuranyl]-2-hydroxyethyl]ester,and Span® 20. CAS Number 1338-39-2.

Sorbitan monooleate, also known as, or similar to, or related to, Span80, is a mixture of the partial esters of sorbitol and its mono- anddianhydrides with edible oleic acid. The constituent in greatestabundance is 1,4-sorbitan monooleate, with a lesser abundance ofisosorbide monooleate, sorbitan dioleate and sorbitan trioleate. CASNumber 1338-43-8.

The surfactant may also be a phosphatidylcholine concentrate. One of theadvantages of using phosphatidylcholine concentrate as a surfactant inthe parenteral abuse resistant liquid, is that it is generally notnecessary to add a stabilizer to the liquid.

A stabilizer can also be used in the parenteral abuse resistant liquid.Examples of such stabilizers include a colloidal anhydrous silica, hardfat and a glycerolester of long chain fatty acid.

For formulations comprising hydrophilic carriers or hydrophilicsolvents, the data shows that colloidal anhydrous silica is generallypreferred. Examples of a hydrophilic carrier or a hydrophilic solventinclude macrogol 400, macrogol 600, macrogol 1500, propylene glycol,glycerol and water.

For formulations comprising lipophilic carriers or lipophilic solvents,the data shows that hard fat or glycelester of long chain fatty acid isgenerally preferred. Examples of a lipophilic carrier include mediumchain triglycerides, medium chain partial glycerides, and a vegetableoil.

A vegetable oil is a triglyceride extracted from a plant. Examples ofsuitable vegetable oils include sesame oil, corn oil, sunflower oil,safflower oil and olive oil. Further, vegetable oils also includecoconut oil, cottonseed oil, palm oil, peanut oil, rapeseed oil, soybeanoil, and mustard oil.

The parenteral abuse resistant liquid may optionally also comprise anypharmaceutically acceptable components so as to solubilize, miscibilize,or suspend the abuse-susceptible active pharmaceutical ingredient. Sucha component is a carrier, generally considered a solvent. The parenteralabuse resistant liquid may comprise more than one carrier. The carrieris any pharmaceutically acceptable carrier that solubilizes the activepharmaceutical ingredient and the other ingredients of the fillcomposition.

Within the scope of the present invention, some compositions act as bothcarriers and surfactants. Thus, the parenteral abuse resistant liquidmay consist only of an abuse-susceptible active pharmaceuticalingredient; a viscosity enhancer or an ion exchange resin; and asurfactant.

The term “water” as used herein means purified water as defined bycompendial standards, or any water which is appropriate for use inpharmaceutical formulations.

The carrier may comply with the pharmaceutical compendial standards.Compendial standards include those listed in a reference, such as theEuropean Pharmacopoeia, Österreichisches Arzneibuch, FarmacopéiaBrasileira, Pharmacopoeia of the People's Republic of China, ČeskýIékopis, Pharmacopoea Bohemica, The Czech Pharmacopoeia, EgyptianPharmacopoeia, Pharmacopée française, Deutsches Arzneibuch, DeutscherArzneimittel Codex, Neues Rezeptur Formularium, Greek Pharmacopoeia,Pharmacopoea Hungarica, Indian Pharmacopoeia, Farmakope Indonesia,Iranian Pharmacopoeia, Farmacopea Ufficiale della Repubblica Italiana,The Japanese Pharmacopoeia, The Korean Pharmacopoeia, Farmacopea de losEstados Unidos Mexicanos, Farmakopea Polska, Farmacopeia Portuguesa,Farmacopeea Romana, State Pharmacopoeia of the Russian Federation,Pharmacopoea Slovaca, Slovenský liekopis, Real Farmacopea Española,Pharmacopoea Helvetica, Thai Pharmacopoeia, The State Pharmacopoeia ofthe Ukraine, British Pharmacopoeia, The United States Pharmacopeia, TheNational Formulary, Pharmacopoeia Vietnamica, Pharmacopoea Jugoslavica,African Pharmacopoeia, and The International Pharmacopoeia.

The carrier of the present invention may be hydrophilic, amphiphilic, orlipophilic. Exemplary solvents include polyethylene glycol, propyleneglycol, medium chain triglycerides, corn oil mono- and diglycerides,poloxamers, refined soybean oil, refined sesame oil, ethanol,phospholipid concentrates, and medium chain partial glycerides.

Examples of the abuse resistant liquid of present invention include ahydrophilic formulation, lipophilic formulation, and amphiphilicphospholipid formulation.

An example of a parenteral abuse resistant liquid comprises an activepharmaceutical ingredient and (i) 40 to 60 wt % macrogol 600; (ii) 15 to25 wt % caprylocaproylmacrogol-8 glycerides; (iii) 3 to 10 wt %colloidal anhydrous silica; (iv) 3 to 6 wt % glycerol; (v) 0.5 to 10 wt% water; and (vi) 2 to 20 wt % ion exchange resin or 0.2 to 0.5 wt %xanthan gum, wherein the weight percent are calculated with respect tothe weight of the parenteral abuse resistant liquid.

Another example of a parenteral abuse resistant liquid comprises anactive pharmaceutical ingredient and (i) 40 to 70 wt % hard fat; (ii) 4to 20 wt % glycerol stearate or glycerol dibehenate; (iii) 10 to 70 wt %medium chain triglycerides; (iv) 4 to 50 wt % polysorbate 80; (v) 4 to15 wt % sorbitol monolaurate; (vi) 3 to 10 wt % macrogolglycerolricinoleate or macrogolglycerol hydroxystearate; (vii) 1 to 5 wt %colloidal anhydrous silica; and (viii) 2 to 5 wt % xanthan gum; whereinthe weight percent are calculated with respect to the weight of theparenteral abuse resistant liquid.

Yet another example of a parenteral abuse resistant liquid comprises anactive pharmaceutical ingredient and (i) 50 to 80 wt %phosphatidylcholine concentrate; (ii) 15 to 25 w %caprylocaproylmacrogol 8 glycerides; (iii) 5 to 10 wt % polysorbate 80;(iv) 0.2 to 5 wt % xanthan gum; (v) 1 to 10 wt % colloidal anhydroussilica; and (vi) 4 to 10 wt % water; wherein the weight percent arecalculated with respect to the weight of the parenteral abuse resistantliquid. The phosphatidylcholine concentrate comprises more than 50 wt %phosphatidylcholine, less than 6 wt % lysophosphatidylcholine, and about35 wt % of polypropylene glycol.

The parenteral abuse resistant liquid of the present invention balancesat least three competing properties: (1) solubilization; (2) abuseresistance; and (3) its release profile. Other additional considerationsinclude long term stability, and ease of processing.

The solubility of the abuse-susceptible active pharmaceutical ingredientmay be determined by mixing equivalent of 25% of the therapeuticallyeffective amount of the abuse-susceptible active pharmaceuticalingredient in the liquid blend. After stirring for 18 hours at 20° C. to25° C., additional 25% of the abuse-susceptible active pharmaceuticalingredient is added. This last step is repeated until the saturationsolubility is reached.

The liquid blend of the present invention exhibits abuse resistance. Inone embodiment of the invention, the abuse resistant fill provides nomore than 33% of the abuse-susceptible active pharmaceutical ingredientfor parenteral delivery. To test the abuse resistance, a weighed aliquotcorresponding to the amount of filling material in a capsule istransferred to a metal tablespoon and mixed with 5 mL of purified waterto create a mixture. This mixture is stirred with a spatula and thenbriefly heated to boiling over an open flame. After allowing the mixtureto cool for about 1 minute, the mixture is filtered through a cigarettefilter. The filtrate is then aspirated into a 5 mL disposable syringeequipped with a 20 gauge, 25 mm long needle.

Another aspect of the present invention is a parenteral abuse resistantliquid that is resistant to alcohol dose dumping. Such a liquid meetsthe requirements on alcohol dose dumping resistance set by the EuropeanMedicines Agency or the Food and Drug Administration on selected newdrug products.

In order to ascertain if simultaneous intake of alcohol and an abuseresistant softgel has an influence on the immediate release dissolutionprofile of the active pharmaceutical ingredient, the in vitrodissolution of selected batches of capsules was tested by exposing suchcapsules to (a) 5 hours 0.1N HCl with 40% absolute ethanol; or (b) 5hours in a pH 4.6 buffer with 40% absolute ethanol; or (c) 5 hours in apH buffer 6.8 with 40% absolute ethanol.

The immediate release in vitro dissolution profiles of Formulation A(described in detail below) over five hours in the three differentdissolution media are comparable, and are not influenced in presence of40% ethanol. Within 30 minutes at least 98% the active pharmaceuticalingredient is released in 0.1 N HCl, 96.3% in the pH 4.6 buffer and 91%in the pH 6.8 buffer. These in vitro dissolution data indicate that noin vivo dose dumping occurs in case of simultaneous intake of alcoholand the abuse resistant dosage form.

Another aspect of the present invention is a parenteral abuse resistantliquid that is resistant to solvent, acidic or aqueous extraction. Inorder to ascertain the resistance to solvent extraction, samples ofFormulations A and B (described in detail below) were mixed thoroughlywith non-polar solvents, and extracted for either 6 or 24 hours.Non-polar solvents included xylene, toluene, and a 40:60 mixture ofpetroleum and benzene. After decanting the non-polar solvent, theresidue was not solid but a turbid slurry. Mixing and boiling theresidue did not result in a solid but also in a slurry that spatteredwhile boiling. This behavior is indicative or suggestive of resistanceto solvent extraction.

In order to ascertain the resistance to aqueous and acidic extraction,the fill mass of 10 capsules was mixed with different amounts ofpurified water (5 mL/caps. and 10 mL/caps.) and extracted for 1, 3 or 5days. Further, the fill mass of 10 capsules was mixed with 20 mL ofmethanol and was extracted for 3 days.

The fill mass of 10 capsules of Formulation A or Formulation B was mixedwith 20 mL of 0.1 N hydrochloric acid and extracted for one day.Comparison solutions of Pseudoephedrine HCl (labeled as API in the tablebelow) were prepared. After an extraction of the formulation/solventmixture, the mixtures were centrifugated and the assay ofpseudoephedrine HCl was analyzed by HPLC. Even after centrifugation thesolutions were turbid. The results of the extraction are presented inthe table below. The results were normalized to a capsule containing1164.8 mg of pseudoephedrine HCl.

Calculated Mass of recoverable Formu- Extraction Pseudoephedrine Samplelation time Solvent HCl 1 A 3 days 5 mL water/capsule 94.8 mg 2 A 3 days10 mL water/capsule 83.6 mg 3 B 3 days 5 mL water/capsule 107.2 mgl 4 B3 days 10 mL water/capsule 89.4 mg 5 API 3 days 50 mL water 1243.7 mg 6A 5 days 5 mL water/capsule 105.0 mg 7 A 5 days 10 mL water/capsule100.5 mg 8 B 5 days 5 mL water/capsule 106.9 mg 9 B 5 days 10 mLwater/capsule 112.5 mg 10 API 5 days 50 mL water 1227.7 mg 11 A 3 days20 mL methanol 847.3 mg 12 B 3 days 20 mL methanol 870.3 mg 13 API 3days 20 mL methanol 1165.6 mg 14 A 1 day 5 mL water/capsule 94.5 mg 15 A1 day 10 mL water/capsule 94.1 mg 16 B 1 day 5 mL water/capsule 97.6 mg17 B 1 day 10 mL water/capsule 71.6 mg 18 API 1 day 50 mL water 1026.0mg 19 B 1 day 20 mL HCl 0.1 mol/L 898.6 mg with neutralisation 20 API 1day 20 mL HCl 0.1 mol/L 1197.3 mg with neutralisation 21 B 1 day 20 mLHCl 0.1 mol/L 493.9 mg without neutralisation 22 API 1 day 20 mL HCl 0.1mol/L 1054.7 mg without neutralisation

The data in the above table indicates that aqueous extraction of theactive pharmaceutical ingredient from either Formulation A or B yieldedpoor recovery of the active pharmaceutical ingredient, indicating thatliquid is resistant to solvent, acidic or aqueous extraction. It alsoappears that the resistance is independent of the volume of water usedto extract the liquid, and of the extraction time.

The parenteral abuse resistant liquid of the present invention isapplicable for use in immediate release formulations or in extendedrelease formulations. Usually, such formulations also include a capsuleshell, and are delivered in a capsule.

The phrase “extended release” refers to a formulation designed torelease a therapeutically effective amount of drug or other active agentsuch as a polypeptide or a synthetic compound over an extended period oftime, with the result being a reduction in the number of treatmentsnecessary to achieve the desired therapeutic effect. An example of theextended release capsule is a capsule that releases about 90% of theactive pharmaceutical ingredient in the gastrointestinal tractthroughout a period of about 12 hours after administration.

The phrase “extended release” also includes formulations that exhibitzero order release (see discussion of Formulation E below), andsustained release formulations. See, for example, G. M. Jantzen, J. R.Robinson Sustained-and Controlled-Release Drug Delivery Systems InModern Pharmaceutics, vol. 72, Marcel Dekker Inc. (1995).

The parenteral abuse resistant liquid formulations that show acceptablesolubility properties and comprise a colloidal anhydrous silica and agum exhibit abuse resistant properties. Such formulations includesolvents such as medium chain triglycerides. Formulations that comprisemedium chain triglycerides, colloidal anhydrous silica, and xanthan gum,also include a polysorbate surfactant.

The polysorbate surfactants in the above formulation that exhibits theabuse resistant properties may include polyoxyethylene (20)sorbitanmonolaurate, polyoxyethylene (20) sorbitan monopalmitate,polyoxyethylene (20) sorbitanmonostearate, and polyoxyethylene (20)sorbitanmonooleate.

The formulations Examples 14, 16 to 18 comprise medium chaintriglycerides (26.4%, 27.3%, 27.9% and 28.2%, respectively), polysorbate80 (49.2%, 50.9%, 52.1%, and 52.7%), Span 20 (12.3%, 12.7%, 13.0%, and13.2%), colloidal anhydrous silica (4.5%, 3.5%), and xanthan gum (4.5%,2.7%). These compositions are yellowish, homogeneous, liquidsuspensions, which formed a gel and non-stable bubbles at boiling withwater. 250 and 1000 g of the fill could hardly be drawn up in thesyringe and formed of a milky foam. Both formulations showed gooddispersability after disintegration of capsules (4.5 minutes).Approximately 80% of the fill was dissolved after 20 to 25 minutes and100% after approx. 30 minutes.

Other solvent and surfactant combinations in the liquid blend that showabuse resistant properties when colloidal anhydrous silica and xanthangum is present, include polyethylene glycol, and a surfactant selectedfrom the group consisting of polyoxyl 40 hydrogenated castor oil,polysorbate surfactant, caprylocaproyl macrogol-8 glyceride, andglycerol. Examples of polyethylene glycol include macrogol 400 andmacrogol 600.

Caprylocaproyl macrogol-8 glycerides (Labrasol) in Examples Nos. 30, 31,and 32 and colloidal anhydrous silica/xanthan gum as gelling agents gaveyellowish homogeneous suspensions, which formed a gel and a partiallypersisting foam at boiling in the water. The solution was notsyringeable but the dispersibility of the gel was bad due to formationof a compact mass after 6 minutes in the dispersion medium.

Abuse resistant properties were also observed by replacing macrogol 400(see Example 35) by macrogol 600 and xanthan gum. An intensive frothingmilky emulsion resulted after boiling with water, which was notsyringeable. Both selected formulations of Examples 35 and 36 wereeasily dispersible in 0.1 N HCl at 100 rpm. 80% of the fill weredissolved after 20 minutes and 100% within 30 minutes.

Furthermore, it was found that the liquid blend comprising aphospholipid concentrate and a polysorbate or caprylocaproyl macrogolglyceride surfactant also exhibited acceptable solubility and abuseresistance. The polysorbate surfactants in the above formulation thatexhibited the abuse resistant properties include polyoxyethylene (20)sorbitanmonolaurate, polyoxyethylene (20) sorbitan monopalmitate,polyoxyethylene (20) sorbitanmonostearate, and polyoxyethylene (20)sorbitanmonooleate. Examples of phospholipid concentrates include Phosal50 PG, and Lipoid PPL 600. For selected formulations, the use of aviscosity enhancer (colloidal anhydrous silica 0.5 to 1.5 wt %) wasfound to be necessary in formulations containing the abuse-susceptibleactive pharmaceutical ingredient in order to achieve tamper resistance.

Yet another combination of liquid blend components that exhibitsolubility and abuse resistance is liquid blend comprising polyethyleneglycol, caprylocaproyl macrogol-8 glycerides, glycerol, a viscosityenhancer, and either a gum or an ion-exchange resin. The viscosityenhancer may be a mixture of colloidal anhydrous silica and a gum.

Two examples of formulations that exhibit the desired properties includePseudoephedrine HCl as the abuse-susceptible active pharmaceuticalingredient. One of the formulations comprises xanthan gum (FormulationB), the other pharmaceutical grade ion exchange resin Amberlite IRP64(Formulation A).

These formulations comprise about 50% to 60% polyethylene glycol, 15% to20% caprylocaproyl macrogol-8 glycerides, 3 to 6% colloidal anhydroussilica, 3 to 6% glycerol, 1% to 2% water.

Formulation A comprises macrogol 600 EP (479.02 mg/capsule, 51.0% offill), caprylocaproyl macrogol-8 glycerides EP (160.00 mg, 17.0%),Colloidal anhydrous Silica EP (45.00 mg, 4.8%), Glycerol, anhydrous EP(47.00 mg, 5.0%), Water, purified, EP (12.50 mg, 1.3%), Amberlite IRP64(80.00 mg, 8.5%) and Pseudoephedrine HCl (116.48 mg, 12.4%).

Formulation B comprises macrogol 600 EP (554.2 mg/capsule, 58.3% offill), caprylocaproyl macrogol-8 glycerides EP (175.00 mg, 18.4%),colloidal anhydrous silica EP (40.00 mg, 4.2%), anhydrous glycerol EP(47.00 mg, 4.9%), purified water, EP (12.50 mg, 1.3%), xanthan gum (5.00mg, 0.5%) and pseudoephedrine HCl (116.48 mg, 12.3%).

Macrogol 600 is hydrophilic solvent for the water soluble drugs.Caprylocaproylmacrogol 8 glycerides are hydrophilic surfactants (HLB 14)and solvents that improve dissolution and bioavailability, and causebubbling at boiling of the capsule fill with water. Colloidal anhydroussilica is a viscosity enhancer in order to stabilize the hydrophile fillsuspension. Glycerol is a plasticizer in the fill to reduce migrationfrom the shell to the fill. Water increases drug solubility, reducesgelling agent concentration and has a positive effect on immediaterelease dissolution properties.

With respect to xanthan gum in formulation B, this hydrogelling agent issuspended in the capsule fill, but at boiling of the capsule fill withhot water, it may form a highly viscous gel. This gel formation reducessyringability and injectability.

With respect to Amberlite IRP64 in formulation A, the HCl salt of thequarternary ammonium ion of the active substance pseudoephedrine HCl maycreate a drug-ion exchange complex with the weak acidic catonic resin(—COOH group) on Amberlite IRP64. This ion pair complex is stable in theformulation, but is immediately released in the stomach environment, asthe —COOH group of the resin has a high affinity to the H⁺ ions presentin the stomach. In addition to the fast release of the abuse-susceptibleactive pharmaceutical ingredient in 0.1 N HCl, an increase of theviscosity at boiling of the formulations containing the Polyacrilexresin was achieved.

The following results have been obtained for in vitro dissolution andthe abuse resistance test (syringability). The immediate releasedissolution (in 0.1 N HCl, at 75 rpm) showed that more than 95% of theactive pharmaceutical ingredient in either of the formulations wasreleased within 30 minutes. Both formulations showed that not more than33% of the pharmaceutically active ingredient was detectable in syringeafter boiling of the capsule fill with 5 mL water. For formulation Bonly about 9.8% of the pseudoephedrine was recovered, and forformulation A only about 12.2% of the pseudoephedrine was recovered.

Three further examples of formulations that exhibit the desiredproperties also included pseudoephedrine HCl as the abuse-susceptibleactive pharmaceutical ingredient. Two of the immediate releaseformulations contained alternative ion exchange resins. Formulation Ccomprised Amberlite IRP69, and Formulation D contained DuoliteAP143/1093. The extended release formulation E comprised Phosal PG incombination with caprylocaproyl macrogol-8 glycerides and xanthan gum.

Formulations C and D contained about 50% to 60% polyethylene glycol, 15%to 20% caprylocaproyl macrogol-8 glycerides, 3% to 6% colloidalanhydrous silica, 3% to 6% glycerol, and 1% to 2% water.

Formulation C contained macrogol 600 EP (479.02 mg/capsule, 51.0% offill), caprylocaproyl macrogol-8 glycerides EP (160.00 mg, 17.0%),colloidal anhydrous silica EP (85.00 mg, 9.6%), anhydrous glycerol EP(47.00 mg, 5.0%), purified water, EP (12.50 mg, 1.3%), Amberlite IRP69(40.00 mg, 4.3%) and pseudoephedrine HCl (116.48 mg, 12.4%).

Formulation D contained macrogol 600 EP (459.02 mg/capsule, 48.8% offill), caprylocaproyl macrogol-8 glycerides EP (160.00 mg, 17.0%),colloidal anhydrous silica EP (65.00 mg, 6.9%), anhydrous glycerol EP(47.00 mg, 5.0%), purified water EP (12.50 mg, 1.3%), Duolite AP143/1093 (80.00 mg, 8.5%), and pseudoephedrine HCl (116.48 mg, 12.4%).

The capsule shell contained glycerol 85% EP 112.15 mg (range 103.18 mgto 121.12 mg), partially hydrated dry substance of sorbitol 31.34 mg(28.83 mg to 33.85 mg), gelatin 160 bloom EP NF (bovine, kosher, Halal)247.96 mg (228.12 to 267.80 mg).

Amberlite IRP69, sodium polystyrene sulfonate USP, an insoluble sodiumsalt of a strong acid and strong base. The mobile exchangeable cation issodium, which can be exchanged by cationic (basic) species independentof pH. The resin binds the active ingredient onto an insoluble polymericmatrix. The active pharmaceutical ingredient is released from the resinin vivo in the gastrointestinal tract with high electrolyteconcentrations.

Duolite AP 143/1093 resin, colestyramine resin, is an insoluble,strongly basic, anion exchange resin and in the chloride form suitableas carrier for acidic, anionic drug substances. The ability to exchangeanions from this styrene/divinylbenzene copolymer with an quarternaryammonium functionality is also largely independent of pH. In addition,colestyramine resin has adsorptive pH independent properties.

The following results of relevant parameters of in vitro dissolution andthe abuse resistance test (“syringeability”) have been obtained. Theimmediate release dissolution (in 0.1 N HCl, at 75 rpm) showed that morethan 90% of the active pharmaceutical ingredient in either of theformulations was dissolved and released within 30 minutes. Bothformulations showed that not more than 33% of the active pharmaceuticalingredient was detected in a syringe after boiling of the capsule fillwith 5 mL water. For formulation C, only about 10.2% of thepseudoephedrine was recovered, and for formulation D, only about 12.1%of the pseudoephedrine was recovered.

Formulation E contained about 50 to 80 wt % phosphatidylcholineconcentrate, 15 to 25 wt % caprylocaproyl macrogol-8 glycerides, 0.2 to5% xanthan gum, and 4 to 10 wt % water.

Formulation F contained Phosal 50 PG (537.02 mg/capsule, 56.5% of fill),caprylocaproyl macrogol-8 glycerides EP (190.00 mg, 20.0%), purifiedwater EP (66.50 mg, 7.0%), xanthan gum EP (40.00 mg, 4.2%) andpseudoephedrine HCl (116.48 mg, 12.3%).

The capsule shell contained propylene glycol 85% EP 78.73 mg (72.43 mgto 85.03 mg), glycerol 85% 35.64 mg (32.62 mg to 38.80 mg); gelatin 195bloom EP NF (bovine) 304.67 mg (280.30 mg to 329.04 mg); titaniumdioxide EP USP 0.96 mg (0.88 mg to 1.037 mg); red iron oxide 0.064 mg(0.059 mg to 0.069 mg), yellow iron oxide 0.90 mg (0.83 mg to 0.97 mg).

The phospholipid concentrate also exhibits gelling in presence of water.Similar to the xanthan gum in formulation B, the phospholipidconcentrate may be partly dissolved in the capsule fill, and at boilingof the capsule fill with hot water it forms a highly viscous gel. Boththe phospholipid concentrate and xanthan gum are susceptible to bubblingon heating with water resulting in formation of a very stable foam.

The active pharmaceutical ingredient is dissolved in the mixture ofpurified water, Phosal 50 PG and caprylocaproylmacrogol glycerides. Thehighly concentrated xanthan gum (4.2%) forms a hydrogel with the liquidblend in the capsule that provides extended release of the activepharmaceutical ingredient over 12 hours after its administration.

The following results of the in vitro dissolution and abuse resistancetest have been obtained. The extended release dissolution over a totalof 12 hours (2 hours in 0.1 N HCl, 2 hours in a pH 4.6 buffer, and 8hours in a pH 6.8 buffer) showed an extended release zero orderdissolution profile. Over a period of 12 hours more than 97% of thepseudoephedrine HCl was released in the dissolution medium. Not morethan 2.2% the pseudoephedrine HCl was detectable in a syringe afterboiling of the capsule fill with 5 mL water.

Another aspect of the present invention is a parenteral abuse resistantcapsule comprising any of the abuse resistant liquids as describedabove.

The capsule is an oral dosage form for delivery of an activepharmaceutical ingredient. The capsule comprises at least a shell (alsoknown as a “capsule shell”) and a fill (also known as a “capsule fill”).The shell completely surrounds the fill so as hold the fill. Thecomposition of the capsule shell is such that it is compatible with thefill.

The parenteral abuse resistant capsule comprises a shell which may becomprised of any suitable material that is known to form a capsule. Inone embodiment of the present invention, the capsule is a hard gelatincapsule. The hard gelatin capsule may be formed and filled in any mannerknown in the art. In one embodiment, the hard gelatin capsule isexclusively designed to optimize liquid filling.

In another embodiment, the capsule is a soft capsule, such as a softgelatin capsule. The shell may be formed from a combination of gelatin,water, and a plasticiser. Type A gelatin, with an isoionic point of 7 to9, is derived from collagen with acid pretreatment. Type B gelatin, withan isoionic point of 4.8 to 5.2, is the result of alkaline pretreatmentof the collagen. Type A gelatin, Type B gelatin or mixtures thereof maybe used to form the capsule shell.

Examples of plasticizers include propylene glycol, glycerol, glycerin,sorbitol, and Anidrisorb.

The shell may be composed of a material that does not include gelatin.Exemplary components of non-gelatin capsules include modified starch,modified cellulose, substances derived from seaweed, and carrageenan. Inone embodiment, the shell is based on a modified starch and carrageenan.An example of such a shell is the OptiShell®, which is a shell derivedfrom plant polysaccharides that are suited for the encapsulation ofhigher melting point fill formulations, and for soft capsules containingsemi-solid matrices for modified release of poorly soluble and/or poorlypermeable drug compounds. The shell may be composed of substances thatmeet the ethical, cultural, dietary, or religious restrictions of thetarget consumer of the capsule such as the Kosher standards or the Halalstandards.

An exemplary capsule shell comprises glycerol 85% EP (106.43 mg, range97.92 mg to 114.94 mg), dry substance of partially hydrogenated sorbitol(Anidrisorb 85/70, 30.87 mg, range 28.40 mg to 33.34 mg); gelatin 160bloom. EP NF (bovine, kosher, Halal, 244.17 mg, range 224.64 mg to263.70 mg).

An exemplary gelatin free shell comprises 142.29 mg (range of 128.06 mgto 156.518 mg) modified maize starch; 46.06 mg (41.46 mg to 50.67 mg)carrageenan, 151.64 mg (136.48 mg to 166.80 mg) partially hydrated drysubstance of sorbitol, 4.17 mg (3.75 to 4.59 mg) anhydrous sodiumhydrogen phosphate, and 15.84 mg (14.26 to 17.42 mg) purified water.

EXPERIMENTAL

Examples 1 to 82 relate to the formulation of the fill ingredientswithout the active pharmaceutical ingredient. These examples provideguidance on formulating the entire fill liquid. Examples 83 to 157disclose abuse resistant liquid comprising various active pharmaceuticalingredients.

Unless otherwise specified, dispersability was tested in 0.1 N HCl witha paddle dissolution apparatus at 100 rpm. One test for abuse resistancewas whether a mixture with 5% water could be drawn up into a syringe.Compositions that could not be drawn up into a syringe or could hardlybe drawn up into the syringe were considered to be abuse resistant.Also, compositions wherein about 33% or less of the pharmaceuticallyactive ingredient could be recovered from the solution drawn up into thesyringe also were considered to be abuse resistant.

Examples 1 to 3: Hard Fat Formulations

Examples 1 to 3 show that formulations based on hard fat are not likelyto be viable abuse resistant formulations.

Example 1

15.8 g of medium chain triglycerides, 2.5 g of hydrogenated soya beanoil, 41.7 g of hard fat, 3.3 g of Povidone K 30, and 3.3 g of polyoxyl40 hydrogenated castor oil were mixed to obtain a homogenous mixture.The mixture was firm at room temperature, and flowable and pourable at30° C. When the mixture was boiled with water (ca. 250 mg of the mixturein 5 mL of water), hard fat separated on cooling down. No air bubbleswere formed at boiling. The aqueous phase was syringeable with a 20gauge needle, and small particles of hard fat were also observed in thesyringe. After disintegration of the shell of lab filled capsules atabout 25 minutes, the fill was dispersed with the remaining fatparticles in the dissolution medium and an oil film on the surface.

Example 2

15.8 g of medium chain triglycerides, 2.5 g of hydrogenated soya beanoil, 41.7 g of hard fat, 3.3 g of Povidone K 30, and 3.3 g ofpolysorbate 80 h were mixed to obtain a homogenous mixture. The mixturewas firm at room temperature, and flowable and pourable at 30° C. Whenthe mixture was boiled with water, hard fat separated on cooling down.No air bubbles were formed at boiling and the aqueous phase wassyringeable, and small particles of hard fat were also observed in thesyringe. After disintegration of the shell at about 25 minutes, the fillwas dispersed with the remaining fat particles in the dissolution mediumand an oil film on the surface.

Example 3

15.8 g of medium chain triglycerides, 2.5 g of hydrogenated soya beanoil, 41.7 g of hard fat, 3.3 g of Povidone K 30, and 3.3 g of polyoxyl35 castor oil were mixed to obtain a homogenous mixture. The mixture wasfirm at room temperature, and flowable and pourable at 30° C. When themixture was boiled with water, hard fat separated on cooling down. Noair bubbles were formed at boiling and the aqueous phase wassyringeable, whereas small particles of hard fat were also observed inthe syringe. After disintegration of the shell at about 25 minutes, thefill was dispersed with the remaining fat particles in the dissolutionmedium and an oil film on the surface.

Examples 4 to 18: Medium Chain Triglyceride Formulations (LFCS Type I,II and III)

By use of medium chain triglycerides as a solvent/carrier andPolysorbate 80 and/or Span 20, Cremophor EL/RH 40 and Labrasol assurfactants, the compositions of Examples 4 to 13 were prepared. Thoseformulations, which were physically stable and showed formation oflittle bubbles at boiling, were syringeable. The compositions ofExamples 14 to 18 show the effect of the addition of gelling agentsxanthan gum and/or colloidal anhydrous silica.

Example 4

45.0 g of medium chain triglycerides, 10.0 g of hydrogenated soya beanoil, and 10.0 g of polyoxyl 40 hydrogenated castor oil were mixed toobtain a homogenous mixture. The mixture was soft, flowable and pourableat room temperature. The sample exhibited a sheen of oil andsedimentation.

Example 5

45.0 g of medium chain triglycerides, 10.0 g of hydrogenated soya beanoil, and 10.0 g of polysorbate 80 were mixed to obtain a homogenousmixture. The mixture was soft, flowable and pourable at roomtemperature. The sample exhibited a sheen of oil and sedimentation.

Example 6

45.0 g of medium chain triglycerides, 10.0 g of hydrogenated soya beanoil, and 10.0 g of polyoxyl 35 castor oil were mixed to obtain ahomogenous mixture. The mixture was soft, flowable and pourable at roomtemperature. The sample exhibited a sheen of oil and sedimentation.

Example 7

10.0 g of medium chain triglycerides and 40.0 g of polysorbate 80 weremixed to obtain a homogenous mixture. The mixture was a clear yellowishsolution. When the solution was boiled with water, no frothing wasobserved.

Example 8

41.0 g of caprylocaproyl macrogol-8 glyceride, 6.5 g of medium chaintriglycerides, and 2.5 g of polyglycerol-6-dioleate were mixed to obtaina clear yellowish solution. Upon addition of water, a white emulsion wasobtained. No frothing was observed upon boiling with water.

Example 9

8.0 g of medium chain triglycerides, 25.6 g of polysorbate 80, and 6.4 gof sorbitan monolaurate were mixed to obtain a homogenous mixture. Themixture was a clear yellowish solution. Upon addition of water, a turbidsolution was obtained. Little frothing was observed upon boiling withwater. The turbid solution could be drawn up into the syringe withlittle frothing.

Example 10

12.0 g of medium chain triglycerides, 22.4 g of polysorbate 80, and 5.6g of sorbitan monolaurate were mixed to obtain a homogenous mixture. Themixture was a clear yellowish solution. Upon addition of water, analmost clear solution was obtained. Little frothing was observed uponboiling with water. The solution could be drawn up into the syringe withlittle frothing.

Example 11

16.0 g of medium chain triglycerides, 19.2 g of polysorbate 80, and 4.8g of sorbitan monolaurate were mixed to obtain a homogenous mixture. Themixture was a clear yellowish solution. Upon addition of water, a turbidsolution was obtained. Little frothing was observed upon boiling withwater. The milky solution could be drawn up into the syringe with littlefrothing.

Example 12

20.0 g of medium chain triglycerides, 16.0 g of polysorbate 80, and 4.0g of sorbitan monolaurate were mixed to obtain a homogenous mixture. Themixture was a clear yellowish solution. Upon addition of water, a whiteemulsion was obtained. Little frothing was observed upon boiling withwater. The milky emulsion could be drawn up into the syringe with littlefrothing.

Example 13

24.0 g of medium chain triglycerides, 12.8 g of polysorbate 80, and 3.2g of sorbitan monolaurate were mixed to obtain a homogenous mixture. Themixture was a clear yellowish solution. Upon addition of water, a whiteemulsion was obtained. Little frothing was observed upon boiling withwater. The milky emulsion could be drawn up into the syringe with littlefrothing.

Example 14

12.0 g of medium chain triglycerides, 22.4 g of polysorbate 80, 5.6 g ofsorbitanmonolaurate, 1.5 g of colloidal anhydrous silica, and 4.0 g ofxanthan gum were mixed to obtain a homogenous yellowish suspension thatwas a pourable liquid. Upon addition of water, the suspension formed agel. Upon boiling with water, frothing was observed, but the foam doesnot persist. The solution could not be drawn up into the syringe.

The yellowish suspension was used to fill a tube-shaped capsule. Thecapsule was then tested for dispersability and after about 20 minutes,about 40% of the fill dispersed.

Example 15

12.0 g of medium chain triglycerides, 22.4 g of polysorbate 80, 5.6 g ofsorbitan monolaurate, and 2.0 g of colloidal anhydrous silica were mixedto obtain a yellowish gel that was almost clear. Upon addition of water,a white emulsion formed. Upon boiling with water, little frothing wasobserved. The milky solution could be drawn up into the syringe.

Example 16

12.0 g of medium chain triglycerides, 22.4 g of polysorbate 80, 5.6 g ofsorbitan monolaurate, 2.0 g of colloidal anhydrous silica, and 2.0 g ofxanthan gum were mixed to obtain a homogenous yellowish suspension thatwas pourable. Upon addition of water, a gel formed. Upon boiling withwater, frothing was observed and the foam does not persist. The milkysolution could hardly be drawn up into the syringe. At a higherconcentration of the suspension (1 g in 5 mL of water), the resultingmixture exhibits very strong frothing, and the mixture could not bedrawn into the syringe. The yellowish suspension was tested fordispersability as in Example 14 and after about 4.5 minutes the capsuleopened; after about 20 to 25 minutes about 80% of the fill dissolved.After about 30 to 35 minutes 100% of the fill was dissolved.

Example 17

12.0 g of medium chain triglycerides, 22.4 g of polysorbate 80, 5.6 g ofsorbitan monolaurate, 1.5 g of colloidal anhydrous silica, and 1.5 g ofxanthan gum were mixed to obtain a homogenous yellowish suspension thatwas pourable. Upon addition of water, a gel formed. Upon boiling withwater, frothing was observed and the foam does not persist. The milkysolution could hardly be drawn up into the syringe. At a higherconcentration of the suspension, the resulting mixture exhibited verystrong frothing, and the mixture would hardly be drawn into the syringe.The foam could be pressed out.

Example 18

12.0 g of medium chain triglycerides, 22.4 g of polysorbate 80, 5.6 g ofsorbitan monolaurate, 1.5 g of colloidal anhydrous silica, and 1.0 g ofxanthan gum were mixed to obtain a homogenous yellowish suspension thatwas pourable. Upon addition of water, a gel formed. Upon boiling withwater, frothing was observed and the foam does not persist. The milkysolution could hardly be drawn up into the syringe. At a higherconcentration of the suspension, the resulting mixture exhibited verystrong frothing, and the mixture could hardly be drawn into the syringe.The foam could be pressed out. The yellowish suspension was tested fordispersability as in Example 14 and after about 4.5 minutes the capsuleopened; after about 20 to 25 minutes about 80% of the fill wasdissolved. After about 30 to 35 minutes 100% of the fill was dissolved.

Examples 19 to 37: Macrogol Formulations (LFCS Type III and IV)

Several different formulations (Example nos. 19 to 26) based on 7:1mixtures of macrogol 400 with medium chain triglycerides or propyleneglycol, polysorbate 80, Span 20, or Cremophor RH 40/EL as surfactantsand colloidal anhydrous silica were prepared. The resulting opalescentto turbid yellowish homogeneous solutions formed emulsions or clearsolutions after boiling with water. No formation of bubbles wasobserved.

By use of xanthan gum as a gelling agent (Example nos. 27 to 29) addedto the macrogol/propylene glycol mixtures, sedimentation and separationin phases resulted.

3:1 mixtures of macrogol 400 with the surfactants Cremophor RH 40,polysorbate 80 and Labrasol (Example Nos. 30 to 32) and colloidalanhydrous silica/xanthan gum as gelling agents were yellowishhomogeneous suspensions, which formed a gel and a partially persistingfoam at boiling in the water. The solution was not syringeable but thedispersibility of the gel was poor due to formation of a compact massafter 6 minutes in the dispersion medium.

A mixture of 30% macrogol 400 with 10% polysorbate 80 or Cremophor RH 40and 2% colloidal silicon dioxide (Example Nos. 33 and 34) formed clear,not fluid gels. After boiling with water the resulting white nonbubbling emulsions were easily syringeable with little frothing. Theformulations showed a good dispersibility (80% after 20 minutes).

Replacement of Span 20 and Polysorbate 80 by Labrasol®, (Caprylo-Caproylmacrogolglycerides) in Example No. 35 gave good results. The clear toyellowish gel formed a white, little bubbling emulsion at boiling withwater. The milky emulsion, though it could be drawn up with the syringe,formed intense bubbles in the syringe. The syringability was reduced byaddition of xanthan gum as an additional gelling agent in Example Nos.36 and 37. Macrogol 400 or macrogol 600 were used.

Example 19

42.5 g of macrogol 400, 6.3 g of medium chain triglycerides, 6.3 g ofpolysorbate 80, and 1.3 g of colloidal anhydrous silica were mixed toobtain an opalescent, yellowish solution. Upon addition of water, awhite emulsion was obtained. Upon boiling with water, no frothing wasobserved.

Example 20

42.5 g of macrogol 400, 6.3 g of medium chain triglycerides, 6.3 g ofpolyoxyl 40 hydrogenated castor oil, and 1.3 g of colloidal anhydroussilica were mixed to obtain an opalescent, yellowish solution. Uponaddition of water, a white emulsion was obtained. Upon boiling withwater, no frothing was observed.

Example 21

42.5 g of macrogol 400, 6.3 g of medium chain triglycerides, 6.3 g ofpolyoxyl 35 castor oil, and 1.3 g of colloidal anhydrous silica weremixed to obtain an opalescent, yellowish solution. Upon addition ofwater, a white emulsion was obtained. Upon boiling with water, nofrothing was observed.

Example 22

38.8 g of macrogol 400, 6.3 g of propylene glycol, 2.5 g of water, 6.3 gof polysorbate 80, and 2.5 g of Povidone K 30 were mixed to obtain apale yellow, turbid solution that separated.

Example 23

38.8 g of macrogol 400, 6.3 g of propylene glycol, 2.5 g of water, 6.3 gof polysorbate 20, and 2.5 g of Povidone K 30 were mixed to obtain ahomogenous pale yellow, turbid solution. Upon addition of water, a clearsolution was obtained. Upon boiling with water, no frothing wasobserved.

Example 24

38.8 g of macrogol 400, 6.3 g of propylene glycol, 2.5 g of water, 6.3 gof polyoxyl 40 hydrogenated castor oil, and 2.5 g of Povidone K 30 weremixed to obtain a homogenous pale yellow, almost clear solution. Uponaddition of water, a clear solution was obtained. Upon boiling withwater, no frothing was observed.

Example 25

38.8 g of macrogol 600, 6.3 g of propylene glycol, 2.5 g of water, 6.3 gof polysorbate 80, and 2.5 g of Povidone K 30 were mixed to obtain apale yellow, turbid solution that separated.

Example 26

38.8 g of macrogol 600, 6.3 g of propylene glycol, 2.5 g of water, 6.3 gof polysorbate 80, and 2.5 g of Povidone K 30 were mixed to obtain apale yellow, turbid solution that separated.

Example 27

35.0 g of macrogol 600, 6.3 g of propylene glycol, 2.5 g of water, 6.3 gof polyoxyl 35 castor oil, and 6.3 g of xanthan gum were mixed to obtaina mixture that separated and sedimented.

Example 28

35.0 g of macrogol 600, 6.3 g of propylene glycol, 2.5 g of water, 6.3 gof polysorbate 20, and 6.3 g of xanthan gum were mixed to provide amixture that separated and sedimented.

Example 29

35.0 g of macrogol 600, 6.3 g of propylene glycol, 2.5 g of water, 6.3 gof polyoxyl 40 hydrogenated castor oil, and 6.3 g of xanthan gum weremixed to obtain a mixture that separated and sedimented.

Example 30

30.0 g of macrogol 400, 10.0 g of polyoxyl 40 hydrogenated castor oil,5.0 g of xanthan gum, and 1.0 g of colloidal anhydrous silica were mixedto obtain a homogeneous yellowish suspension that was pourable. Thesuspension formed a gel when mixed with water. Upon boiling, the gelfrothed and the foam partially persisted. The resulting solution couldnot be drawn up in a syringe. The yellowish suspension was tested fordispersability as in Example 14 and after about 60 minutes the fill wasa compact mass with less than 50% of the fill dissolved.

Example 31

30.0 g of macrogol 400, 10.0 g of polysorbate 80, 5.0 g of xanthan gum,and 1.0 g of colloidal anhydrous silica were mixed to obtain ahomogeneous yellowish suspension that was pourable. The suspensionformed a gel when mixed with water. Upon boiling, the gel frothed andthe foam did not persist. The resulting solution could not be drawn upin a syringe. The yellowish suspension was tested for dispersability andafter about 60 minutes the fill was a compact mass with less than 50% ofthe fill dissolved.

Example 32

30.0 g of macrogol 400, 10.0 g of caprylocaproyl macrogol-8 glyceride,5.0 g of xanthan gum, and 1.0 g of colloidal anhydrous silica were mixedto obtain a homogeneous yellowish suspension that was pourable. Thesuspension formed a gel when mixed with water. Upon boiling, the gelfrothed, wherein the foam partially persisted. The resulting solutioncould not be drawn up in a syringe. The yellowish suspension was testedfor dispersability and after about 60 minutes the fill was a compactmass with less than 50% of the fill dissolved.

Example 33

30.0 g of macrogol 400, 10.0 g of polyoxyl 40 hydrogenated castor oil,and 2.0 g of colloidal anhydrous silica were mixed to obtain a colorlessgel that was pourable. The gel formed a white emulsion when mixed withwater. Upon boiling, no frothing was observed. The resulting solutioncould not be drawn up in a syringe. The formulation was tested fordispersability and after about 20 minutes, about 90% of the filldispersed.

Example 34

30.0 g of macrogol 400, 10.0 g of polysorbate 80, and 2.0 g of colloidalanhydrous silica were mixed to obtain a turbid yellowish gel that wasbarely pourable. The gel formed a white emulsion when mixed with water.Upon boiling, no frothing was observed. The resulting solution could bedrawn up in a syringe. The formulation was tested for dispersability andafter about 20 minutes, about 80% of the fill dispersed.

Example 35

30.0 g of macrogol 400, 10.0 g of caprylocaproyl macrogol-8 glyceride,and 2.0 g of colloidal anhydrous silica were mixed to obtain a clearyellowish gel that was pourable. The gel formed a white emulsion whenmixed with water. Upon boiling, strong frothing was observed. Theresulting solution could be drawn up in a syringe. For the higherconcentration of the formulation in water, the resulting milky emulsionexhibits strong frothing and could be drawn up into the syringe. Thedispersability test showed that after about 20 minutes 80% of the fillwas dissolved, and within 30 minutes the entire fill was dissolved.

Example 36

30.0 g of macrogol 600, 10.0 g of caprylocaproyl macrogol-8 glyceride,2.0 g of colloidal anhydrous silica, and 0.8 g of xanthan gum were mixedto obtain a turbid yellowish gel that was barely pourable. The mixtureformed a gel when mixed with water. Upon boiling, little frothing wasobserved. The resulting mixture could be drawn up in a syringe. For thehigher concentration of the formulation in water, the resulting mixturecould not be drawn up into the syringe, and strong frothing wasobserved.

Example 37

30.0 g of macrogol 400, 10.0 g of caprylocaproyl macrogol-8 glyceride,2.0 g of colloidal anhydrous silica, and 2.0 g of xanthan gum were mixedto obtain a turbid yellowish gel that was barely pourable. The mixtureformed a gel when mixed with water. Upon boiling, little frothing wasobserved. The resulting mixture could be drawn up in a syringe. For thehigher concentration of the formulation in water, the resulting mixturecould not be drawn up into the syringe, and exhibited strong frothing.The dispersability test showed that after about 20 minutes 80% of thefill was dissolved, and within 30 minutes the entire fill was dissolved.

Examples 38 to 46: Medium Chain Partial Glycerides Formulations (LFCSType II and III a/b)

Six formulations (Example Nos. 38 to 43) were prepared based on mediumchain partial glycerides as solvents in combination with differentsurfactants. The yellowish solutions formed white non-frothing emulsionswith water. By addition of a mixture of propylene glycol and Lipoid PPL600 (Example Nos. 44 to 46) a non-persisting foam was obtained atbubbling. However, the emulsions were easily syringeable. Thisdemonstrates the lack of suitability of medium chain partial glyceridesas suitable solvents in fills for abuse resistant capsules.

Example 38

33.8 g of medium chain partial glycerides, 6.3 g of polysorbate 80, and3.8 g of Povidone K 30 were mixed to obtain a clear pale yellowsolution. The mixture formed a grey emulsion when mixed with water. Uponboiling, no frothing was observed.

Example 39

33.8 g of medium chain partial glycerides, 6.3 g of polysorbate 20, and3.8 g of Povidone K 30 were mixed to obtain a clear pale yellowsolution. The mixture formed a grey translucent emulsion when mixed withwater. Upon boiling, no frothing is observed.

Example 40

33.8 g of medium chain partial glycerides, 6.3 g of polyoxyl 40hydrogenated castor oil, and 3.8 g of Povidone K 30 were mixed to obtaina clear pale yellow solution. The mixture formed a white emulsion whenmixed with water. Upon boiling, no frothing was observed.

Example 41

25.0 g of medium chain partial glycerides, 18.0 g of polysorbate 80, and18.0 g of propylene glycol were mixed to obtain a clear pale yellowsolution. The mixture formed a white emulsion when mixed with water.Upon boiling, no frothing was observed. The milky emulsion could bedrawn up into the syringe.

Example 42

25.0 g of medium chain partial glycerides, 18.0 g of polysorbate 20, and18.0 g of propylene glycol were mixed to obtain a clear pale yellowsolution. The mixture formed a white emulsion when mixed with water.Upon boiling, no frothing was observed.

Example 43

25.0 g of medium chain partial glycerides, 6.3 g of polysorbate 20, and3.8 g of Povidone K 30 were mixed to obtain a clear pale yellowsolution. The mixture formed a grey translucent emulsion when mixed withwater. Upon boiling, no frothing was observed.

Example 44

35.0 g of medium chain partial glycerides and 15.0 g of lipoid PPL-600were mixed to obtain a clear reddish brown solution. When mixed withwater, the mixture spreads, but does not form an emulsion. Upon boiling,frothing was observed, but it did not persist. The milky emulsion couldbe drawn up into the syringe.

Example 45

25.0 g of medium chain partial glycerides, 15.0 g of lipoid PPL-600, and10.0 g of propylene glycol were mixed to obtain a clear reddish brownsolution. When mixed with water, the mixture spreads, but does not forman emulsion. Upon boiling, frothing was observed, but it did notpersist. The milky emulsion could be drawn up into the syringe.

Example 46

20.0 g of medium chain partial glycerides, 10.0 g of lipoid PPL-600, and20.0 g of propylene glycol were mixed to obtain a clear reddish brownsolution. When mixed with water, the mixture spreads, but does not forman emulsion. Upon boiling, frothing was observed, but it did notpersist. The milky emulsion could be drawn up into the syringe.

Examples 47 to 65: Phospholipid Formulations (LFCS Type II and III a/b)

Formulations of Example Nos. 47 to 55 were based on Lipoid PPL 600 (amixture of phospholipids (76% PC) with medium chain triglycerides, soyabean oil, tocopherol and glycerol-fatty acid esters) Mixtures withmacrogol were physically not stable and separated into two phases. In1:1 to 6:1 mixtures with propylene glycol and polysorbate 80 (ExampleNos. 52 to 55) clear reddish brown solutions resulted, and formed awhite emulsion with a non-persisting foam at boiling. The emulsions ofthe formulations of Example Nos. 54 and 55 were not syringeable understrong foaming; both formulations were easily dispersed after about 15minutes in the dissolution medium.

Mixtures of Lipoid PPL 600 with propylene glycol were chosen as thealternative to phospholipid concentrate Phosal 50 PG, which containsapprox. 56% phospholipids and 36% propylene glycol, 3% mono- anddiglycerides and 2.4% soya fatty acids plus 2% ethanol as carriers.

The formulations of Example Nos. 56 to 58 as 9:1 mixtures of Phosal 50PG with polysorbate 80, Span 20 and Cremophor RH 40 were clear yellowishsolutions which formed a gelling emulsion with a partially persistingfoam at boiling. By use of 250 mg of fill mass, the fill emulsion wassyringeable but exhibited intensive formation of air bubbles. 1000 mg offormulation Example No. 56 could not be drawn up in the syringe.

By addition of colloidal anhydrous silica (Example Nos. 59, 64, and 65),the frothing suspension could hardly be drawn up in the syringe due to ahigher viscosity and formation of air bubbles.

Additional xanthan gum (Example No. 60) was added and the boiledemulsion separated in two phases. Based on the miscibility results ofphosal (surfactant mixtures with ethanol) and water, 10% water(formulation of Example No. 61) or mixtures of ethanol and water(formulations of Example Nos. 62 and 63) were added to the Phosal 50PG/polysorbate 80 combinations. The clear to turbid yellow solutionsformed partially gelling emulsions with bubbles at boiling. Thesyringability of 1000 mg of these formulations was intensively reducedby formation of very strong bubbles.

Example 47

25.0 g of lipoid PPL-600, and 25.0 g of macrogol 600 were mixed toobtain a mixture that separates and solids appear within one day ofstanding.

Example 48

25.0 g of lipoid PPL-600, and 25.0 g of macrogol 400 were mixed toobtain a mixture that separates after one day of standing.

Example 49

25.0 g of lipoid PPL-600, and 25.0 g of propylene glycol were mixed toobtain a mixture that separates and solids appear within one day ofstanding.

Example 50

10.0 g of lipoid PPL-600, 10.0 g of macrogol 600, and 5.0 g of mediumchain partial glycerides were mixed to obtain a mixture that separates.

Example 51

10.0 g of lipoid PPL-600, 10.0 g of macrogol 400, and 5.0 g of mediumchain partial glycerides were mixed to obtain a mixture that separates.

Example 52

10.0 g of lipoid PPL-600, 10.0 g of propylene glycol, and 5.0 g ofmedium chain partial glycerides were mixed to obtain a clear reddishbrown solution. When mixed with water, a yellowish emulsion formed. Uponboiling, frothing was observed, but it did not persist. The milkyemulsion could be drawn up into the syringe.

Example 53

12.5 g of lipoid PPL-600, 18.8 g of polysorbate 80, and 18.8 g ofpropylene glycol were mixed to obtain a clear reddish brown solution.When mixed with water the mixture turns turbid. Upon boiling, littlefrothing was observed. The turbid emulsion could be drawn up into thesyringe.

Example 54

25.0 g of lipoid PPL-600, 12.5 g of polysorbate 80, and 12.5 g ofpropylene glycol were mixed to obtain a clear yellow-brown solution.When mixed with water a white emulsion formed. Upon boiling, littlefrothing was observed, and the foam did not persist. The milky emulsioncould be drawn up into the syringe.

Example 55

37.5 g of lipoid PPL-600, 6.3 g of polysorbate 80, and 6.3 g ofpropylene glycol were mixed to obtain a clear reddish-brown solution.When mixed with water a white emulsion formed. Upon boiling, frothingwas observed, and the foam partially persisted. It was very difficult todraw up the milky emulsion into the syringe.

Example 56

20.0 g of Phosal 50 PG and 2.0 g of polysorbate 80 were mixed to obtaina clear yellow solution. A yellowish emulsion formed when mixed withwater, partially forming a gel. Upon boiling, frothing was observed, andthe foam partially persisted. Although it was possible to draw thefrothy milky emulsion obtained after boiling into the syringe, for thehigher concentration, very strong frothing was observed, and the milkyemulsion could not be drawn into the syringe. The dispersability testshowed that after about 10 to 15 minutes 100% of the fill was finelydispersed.

Example 57

20.0 g of Phosal 50 PG and 2.0 g of polyoxyl 40 hydrogenated castor oilwere mixed to obtain a clear yellow solution. A yellowish emulsionformed when mixed with water, partially forming a gel. Upon boiling,frothing was observed, and the foam partially persisted. The resultingmilky emulsion could be drawn into the syringe. The dispersability testshowed that after about 15 minutes 100% of the fill was dispersed.

Example 58

20.0 g of Phosal 50 PG and 2.0 g of sorbitanmonolaurate were mixed toobtain a clear yellow solution. A yellowish emulsion formed when mixedwith water, partially forming a gel. Upon boiling, frothing wasobserved, and the foam partially persisted. The resulting milky emulsioncould be drawn into the syringe. The dispersability test showed thatafter about 15 minutes 100% of the fill was dispersed.

Example 59

20.0 g of Phosal 50 PG, 2.0 g of polysorbate 80, and 1.5 g of colloidalanhydrous silica were mixed to obtain a clear yellow solution. Ayellowish emulsion formed when mixed with water, partially forming agel. Upon boiling, frothing was observed, and the foam partiallypersisted. It was difficult to draw the milky emulsion into the syringe.

Example 60

20.0 g of Phosal 50 PG, 2.0 g of polysorbate 80, 1.5 g of colloidalanhydrous silica, and 1.5 g of xanthan gum were mixed to obtain a yellowsuspension. A yellowish emulsion formed when mixed with water, partiallyforming a gel. Upon boiling, frothing was observed, and the foampartially persisted. It was difficult to draw the milky emulsion intothe syringe. At the higher concentrations, the formulation separates,and the aqueous phase could be drawn into the syringe.

Example 61

9.0 g of Phosal 50 PG, 1.0 g of polysorbate 80, and 1.0 g of water weremixed to obtain a turbid yellow suspension. A yellowish emulsion formedwhen mixed with water, partially forming a gel. Upon boiling, frothingwas observed, and the foam partially persisted. Although it was possibleto draw the frothy milky emulsion obtained after boiling into thesyringe, for the higher concentration, very strong frothing wasobserved, and the milky emulsion could not be drawn into the syringe.The dispersability test showed that after about 20 minutes 100% of thefill was finely dispersed.

Example 62

9.0 g of Phosal 50 PG, 1.0 g of polysorbate 80, 0.75 g of water, and0.25 g of ethanol were mixed to obtain an almost clear yellow solution.A yellowish emulsion formed when mixed with water, partially forming agel. Upon boiling, frothing was observed, and the foam partiallypersisted. The milky emulsion could be drawn into the syringe.

Example 63

9.0 g of Phosal 50 PG, 1.0 g of polysorbate 80, 0.5 g of water, and 0.5g of ethanol were mixed to obtain a clear yellow suspension. A yellowishemulsion formed when mixed with water, partially forming a gel. Uponboiling, frothing was observed, and the foam partially persisted.Although it was possible to draw the frothy milky emulsion obtainedafter boiling into the syringe, for the higher concentration, verystrong frothing was observed, and the milky emulsion could not be drawninto the syringe. The dispersability test showed that after about 10minutes 100% of the fill was finely dispersed.

Example 64

20.0 g of Phosal 50 PG, 2.0 g of sorbitan monolaurate, and 1.5 g ofcolloidal anhydrous silica were mixed to obtain an almost clear yellowsuspension. A yellowish emulsion formed when mixed with water, partiallyforming a gel. Upon boiling, frothing was observed, and the foampartially persisted. It was very difficult to draw the frothy milkyemulsion into the syringe.

Example 65

20.0 g of Phosal 50 PG, 2.0 g of sorbitan monolaurate, and 1.5 g ofcolloidal anhydrous silica and 1.5 g of xanthan gum were mixed to obtaina yellow suspension. A yellowish emulsion formed when mixed with water,partially forming a gel. Upon boiling, frothing was observed, and thefoam partially persisted. It was very difficult to draw the frothy milkyemulsion into the syringe.

Example 66

10.0 g of propylene glycol monolaurate and 5.0 g of Polyoxyl 40hydrogenated castor oil were mixed to obtain a white, turbid mixture,which separated after approximately 2 days. A flocculent emulsion formedwhen mixed with water. No frothing was observed upon boiling.

Example 67

10.0 g of propylene glycolmonolaurate and 5.0 g of Labrafil M 2125 CSwere mixed to obtain a clear yellowish solution. The solution separateswhen mixed with water. No frothing was observed upon boiling.

Example 68

10.0 g of propylene glycolmonolaurate and 5.0 g of polysorbate 80 weremixed to obtain a clear yellowish solution. A white emulsion formed whenthe solution was mixed with water. No frothing was observed uponboiling.

Example 69

10.0 g of propylene glycolmonolaurate and 5.0 g ofcaprylocaproylmacrogol-8 glyceride were mixed to obtain a clearcolorless solution. A white emulsion formed when the solution was mixedwith water. No frothing was observed upon boiling.

Example 70

10.0 g of propylene glycolmonolaurate and 5.0 g of lipoid PPL-600 weremixed to obtain a clear yellowish solution. Upon addition of water, thesolution partially formed a gel and separated. No frothing was observedupon boiling.

Example 71

10.0 g of propylene glycolmonolaurate and 5.0 g ofmacrogol-32-glycerollarate were mixed to obtain a white solid mass.

Example 72

2.0 g of gelucire 44/14 and 8.0 g of lipoid PPL-600 were mixed to obtaina yellow-brown solid mass.

Example 73

2.0 g of gelucire 44/14 and 8.0 g of Labrafil M 2125 CS were mixed toobtain a turbid, yellowish, pasty liquid that separated. Upon additionof water, a white emulsion formed. No frothing was observed uponboiling.

Example 74

2.0 g of gelucire 44/14 and 8.0 g of medium chain partial glycerideswere mixed to obtain a clear yellowish solution. Upon addition of water,a white emulsion formed. No frothing was observed upon boiling.

Example 75

2.0 g of gelucire 44/14 and 8.0 g of macrogol 600 were mixed to obtain awhite solid mass.

Example 76

2.0 g of gelucire 44/14 and 8.0 g of propylene glycolmonolaurate weremixed to obtain a white, turbid solution that separated. Upon additionof water, a white emulsion formed. No frothing was observed uponboiling.

Example 77

2.0 g of gelucire 44/14 and 8.0 g of corn oil mono-/di-/tri-glycerideswere mixed to obtain a clear yellowish solution that solidifies after 1to 2 days. Upon addition of water, a white emulsion formed. No frothingwas observed upon boiling.

Example 78

25.0 g of polysorbate 80, 12.5 g of ethanol, and 12.5 g of propyleneglycol were mixed to obtain a clear yellowish solution. Upon addition ofwater, a clear solution formed. Frothing was observed upon boiling, butthe foam does not persist.

Example 79

5.0 g of macrogol-32-glycerollaurate, 37.5 g of polyglycerol-6-dioleate,and 20.0 g of propylene glycol were mixed to obtain a mixture thatseparates.

Example 80

10.0 g of macrogol-32-glycerollaurate, 10.0 g of polyglycerol-6-diolate,and 20.0 g of propylene glycol were mixed to obtain a mixture thatseparates, and partly solidifies.

Example 81

15.0 g of macrogol-32-glycerollaurate, 5.0 g of polyglycerol-6-dioleate,and 20.0 g of propylene glycol were mixed to obtain a mixture thatseparates, and partly solidifies.

Example 82

25.0 g of polysorbate 80 and 25.0 g of glyceryl-monocaprate/-caprylatewere mixed to obtain a clear yellowish solution. Upon mixing with water,a white emulsion if obtained. Little frothing was observed upon boiling.

Examples 83 to 93: Lipophilic Pseudoephedrine HCl Formulations

Lipophilic formulations of Examples 83 to 93 provide abuse resistantsoftgel formulations for highly lipophilic actives. Lipid based fillformulations (LFCS I and II) were developed containing hard fat andmedium chain triglycerides as a lipid matrix and xanthan gum as aviscosity enhancing agent. The formulations differed regarding theirconcentrations of hard fat (0 to 62.2 wt %), medium chain triglycerides(0 to 62.2 wt %), surfactant (5.0 to 45.6 wt %), xanthan gum (1.1 to 4.4wt %), and colloidal anhydrous silica (0 to 1.7 wt %). Polysorbate 80,sorbitan monooleate, single and in mixtures and macrogolglycerolricinoleate (Kolliphor EL) were used as surfactants.

These lipophilic formulations, especially those containing highconcentrations of hard fat, were developed based on the initial resultsof non complaint IR dissolution properties with the objective of anextended release profile. Some formulations show unexpected IR releaseprofiles from lab filled softgels containing 116.48 mg pseudoephedrineHCl in 870 to 900 mg of fill.

Working Example 83

14.6 g of medium chain triglycerides, 27.3 g of polysorbate 80, 6.7 g ofSorbitan monolaurate (SPAN 20), 1.0 g of colloidal anhydrous silica, 2.7g of xanthan gum, and 7.8 g of pseudoephedrine HCl were mixed to obtaina beige, homogenous, soft, flowable, pourable suspension that frothedupon boiling, and formed a gel. It could hardly be drawn up into thesyringe, 7.8% pseudoephedrine HCl was detected. Within 30 minutes, about93.9% of pseudoephedrine HCl was released in 0.1 N HCl.

Comparative Example 84

9.2 g of medium chain triglycerides, 37.3 g of hard fat, 3.0 g ofpolysorbate 80, 2.7 g of xanthan gum, and 7.8 g of pseudoephedrine HClwere mixed to obtain an off-white suspension that was pourable andflowable at 30° C., but was a solid at room temperature

Comparative Example 85

14.6 g of hard fat, 27.3 g of polysorbate 80, 6.7 g of sorbitanmonolaurate/SPAN 20, 1.0 g of colloidal anhydrous silica, 2.7 g ofxanthan gum, and 7.8 g of pseudoephedrine HCl were mixed to obtain anoff-white suspension that was pourable and flowable at 30° C., but was asolid at room temperature.

Comparative Example 86

35.2 g of hard fat, 6.7 g of polysorbate 80, 6.7 g of sorbitanmonolaurate/SPAN 20, 1.0 g of colloidal anhydrous silica, 2.7 g ofxanthan gum, and 7.8 g of pseudoephedrine HCl were mixed to obtain anoff white suspension that was pourable and flowable at 30° C., but wasfirm at room temperature. After boiling with water, it could hardly bedrawn up into the syringe; 5.8% pseudoephedrine HCl was detected. Within30 minutes 87.6% of pseudoephedrine HCl was released in 0.1 N HCl.

Comparative Example 87

9.2 g of medium chain triglycerides, 34.3 g of hard fat, 6.0 g ofpolysorbate 80, 2.7 g of xanthan gum, and 7.8 g of pseudoephedrine HClwere mixed to obtain an off white suspension that was pourable andflowable at 30° C., but was firm at room temperature. After boiling withwater, it could hardly be drawn up into the syringe; 3.2% ofpseudoephedrine HCl was detected. Within 30 minutes, 100.5% ofpseudoephedrine HCl was detected as released in 0.1 N HCl.

Comparative Example 88

9.2 g of medium chain triglycerides, 37.3 g of hard fat, 3.0 g ofmacrogol glycerol ricinoleate, 2.7 g of xanthan gum, and 7.8 g ofpseudoephedrine HCl were mixed to obtain an off white suspension thatwas pourable and flowable at 30° C., but was firm at room temperature.It could hardly be drawn up into the syringe; 8.1% pseudoephedrine HClwas detected. Within 30 minutes, 111% of pseudoephedrine HCl wasdetected as released in 0.1 N HCl.

Comparative Example 89

35.2 g of hard fat, 6.7 g of polysorbate 80, 6.7 g of sorbitanmonolaurate/SPAN 20, 1.0 g of colloidal anhydrous silica, 2.7 g ofxanthan gum, and 7.8 g of pseudoephedrine HCl were mixed to obtain anoff white suspension that was pourable and flowable at 30° C., but wasfirm at room temperature.

Comparative Example 90

9.2 g of medium chain triglycerides, 34.3 g of hard fat, 6.0 g ofpolysorbate 80, 2.7 g of xanthan gum, and 7.8 g of pseudoephedrine HClwere mixed to obtain an off white suspension that was pourable andflowable at 30° C., but was firm at room temperature.

Comparative Example 91

14.6 g of medium chain triglycerides, 27.3 g of polysorbate 80, 6.7 g ofsorbitan monolaurate/SPAN 20, 1.0 g of colloidal anhydrous silica, 0.7 gof xanthan gum, and 7.8 g of pseudoephedrine HCl were mixed to obtain abeige suspension that was homogenous, soft, flowable, and pourable.

Comparative Example 92

43.7 g of medium chain triglycerides, 82.0 g of polysorbate 80, 20.0 gof sorbitan monolaurate/SPAN 20, 3.0 g of colloidal anhydrous silica,2.0 g of xanthan gum, and 23.3 g of pseudoephedrine HCl were mixed toobtain a beige suspension that homogenous, soft, flowable, and pourable.

Working Example 93

9.2 g of medium chain triglycerides, 37.3 g of hard fat, 3.0 g ofpolysorbate 80, 2.7 g of xanthan gum, 7.8 g of pseudoephedrine HCl weremixed to obtain an off-white suspension that was pourable, flowable at30° C., but firm at room temperature. After boiling with water it couldhardly be drawn up into the syringe; 8.3% pseudoephedrine HCl wasdetected. Within 120 minutes 49.2% of pseudoephedrine HCl was releasedin 0.1 N HCl, after 240 minutes 92.6% of pseudoephedrine HCl wasreleased in a pH 4.6 buffer. After 720 minutes 97.8% of pseudoephedrineHCl was released in a pH 6.8 buffer.

Examples 94 to 100: Lipophilic Formulations

In order to achieve an extended release dissolution profile mixtures of5 to 20% Compritol 888 ATO (glycerol dibehenate) or Precirol ATO 5(glyceryl stearate) with medium chain triglycerides were prepared bymelting of such lipid components at 60° C. and cooling down by stirringto room temperature. These solid or semi-solid lipid matrices wereincorporated into formulations based on medium chain triglycerides as alipid excipient, polysorbate 80 as a surfactant and xanthan gum as agelling, viscosity enhancing agent.

The use of Precirol ATO 5 in some of the examples below shows anexcellent immediate release profile: for example, for the formulation ofExample 95, within 30 minutes, about 90.7% of pseudoephedrine HCl wasreleased.

Comparative Example 94

38.2 g of medium chain triglycerides, 8.0 g of Precirol® ATO 5 (glyceryldistearate) 2.3 g of polysorbate 80, 0.3 g of xanthan gum, and 5.8 g ofpseudoephedrine HCl were mixed to obtain an off-white suspension thatwas pourable, flowable at 40° C., but firm at room temperature. The IRprofile showed that 90.7% of pseudoephedrine HCl was released.Syringeability in subsequent work was optimized by increasing thexanthan gum loading level.

Comparative Example 95

28.7 g of medium chain triglycerides, 8.0 g of Compritol 888ATO, 2.3 gof polysorbate 80, 0.3 g of xanthan gum, and 5.8 g of pseudoephedrineHCl were mixed to obtain an off-white suspension that was pourable,flowable at 40° C., but firm at room temperature.

Comparative Example 96

34.4 g of medium chain triglycerides, 4.5 g of Compritol 888ATO, 2.3 gof polysorbate 80, 0.3 g of xanthan gum, and 5.8 g of pseudoephedrineHCl were mixed to obtain an off-white suspension that was pourable,flowable at 40° C., but firm at room temperature.

Comparative Example 97

36.7 g of medium chain triglycerides, 2.3 g of Compritol 888ATO, 2.3 gof polysorbate 80, 0.3 g of xanthan gum, and 5.8 g of pseudoephedrineHCl were mixed to obtain an off-white suspension that was pourable,flowable at 40° C., but firm at room temperature.

Comparative Example 98

13.2 g of medium chain triglycerides, 19.5 g of Hard Fat, 2.3 g ofCompritol 888ATO, 2.3 g of polysorbate 80, 2.0 g of xanthan gum, and 5.8g of pseudoephedrine HCl were mixed to obtain an off-white suspensionthat was pourable, flowable at 40° C., but firm at room temperature.

Comparative Example 99

43.2 g of medium chain triglycerides, 6.0 g of Compritol 888ATO, 3.0 gof polysorbate 80, 2.7 g of xanthan gum, and 7.8 g of pseudoephedrineHCl were mixed to obtain an off-white suspension that was pourable,flowable at 40° C., but firm at room temperature. The formulation couldhardly be drawn up into the syringe.

Comparative Example 100

43.2 g of medium chain triglycerides, 6.0 g of Precirol ATO 5, 3.0 g ofpolysorbate 80, 2.7 g of xanthan gum, and 7.8 g of pseudoephedrine HClwere mixed to obtain an off-white suspension that was pourable, flowableat 40° C., but firm at room temperature. The formulation could hardly bedrawn up into the syringe.

Examples 101 to 117: Phosal Formulations

The compositions of Example Nos. 101, 102, 104 to 106, 108, and 109 arePhosal/polysorbate 80/collodial anhydrous silica formulations. Theseformulations exhibit a release from lab filled capsules containing116.48 mg pseudoephedrine HCl in 900 to 950 mg of fill, that was slowerthan immediate release, and was faster than the extended releaseformulations 107, 116 and 117, that exhibit a sustained releasedissolution profile over 12 hours. An increase of the colloidalanhydrous silica concentration to 20 mg (2.2%) leads to a slower releaseprofile.

Working Example 101

41.9 g of Phosal 50 PG, 4.7 g of polysorbate 80, 4.7 g of purifiedwater, 1.0 g of colloidal anhydrous silica, and 7.8 g of pseudoephedrineHCl were mixed to obtain a yellow gel that was homogenous, soft,flowable, pourable, and almost clear. The mixture frothed on boiling,and formed a gel, which could hardly be drawn up into the syringe.

Working Example 102

41.9 g of Phosal 50 PG, 4.7 g of polysorbate 80, 4.7 g of purifiedwater, 0.7 g of colloidal anhydrous silica, and 7.8 g of pseudoephedrineHCl were mixed to obtain a yellow gel that was homogenous, soft,flowable, pourable, and almost clear. The mixture frothed on boiling,and formed a gel, which could hardly be drawn up into the syringe. 16.7%pseudoephedrine HCl was detected. Within 30 minutes, 88.6% ofpseudoephedrine HCl was released in 0.1N HCl.

Working Example 103

41.9 g of Phosal 50 PG, 5.0 g of polysorbate 80, 5.0 g of purifiedwater, 0.3 g of xanthan gum, and 7.8 g of pseudoephedrine HCl were mixedto obtain a yellow gel that was homogenous, soft, flowable, pourable,and was turbid. The mixture frothed on boiling, and formed a gel, whichcould hardly be drawn up into the syringe.

Working Example 104

41.6 g of Phosal 50 PG, 4.7 g of polysorbate 80, 2.3 g of purifiedwater, 2.3 g of Ethanol, anhydrous, 1.3 g of colloidal anhydrous silica,and 7.8 g of pseudoephedrine HCl were mixed to obtain a yellow gel thatwas homogenous, soft, flowable, pourable, and almost clear. The mixturefrothed on boiling, and formed a gel, which could hardly be drawn upinto the syringe.

Working Example 105

46.2 g of Phosal 50 PG, 4.7 g of polysorbate 80, 1.3 g of colloidalanhydrous silica, and 7.8 g of pseudoephedrine HCl were mixed to obtaina yellow gel that was homogenous, soft, flowable, pourable, and almostclear. The mixture frothed on boiling, and formed a gel, which couldhardly be drawn up into the syringe.

Working Example 106

40.2 g of Phosal 50 PG, 5.0 g of polysorbate 80, 5.7 g of purifiedwater, 1.3 g of colloidal anhydrous silica, and 7.8 g of pseudoephedrineHCl were mixed to obtain a yellow gel that was homogenous, soft,flowable, pourable, and was turbid. The mixture frothed on boiling, andformed a gel, which could hardly be drawn up into the syringe.

Working Example 107

37.6 g of Phosal 50 PG, 12.7 g of caprylocaproyl macrogol-8 glycerides,2.7 g of purified water, 2.7 g of xanthan gum, and 7.8 g ofpseudoephedrine HCl were mixed to obtain a yellow gel that washomogenous, soft, flowable, pourable, and was turbid. The mixturefrothed on boiling, and formed a gel, which could hardly be drawn upinto the syringe. 7.4% of pseudoephedrine HCl were detected in thesyringe. 25.0% of pseudoephedrine HCl was released from a lab filledsoftgel capsule containing 116.48 mg of pseudoephedrine HCl in 950 mg offill after 2 hours in 0.1 N HCl, 46.3% after 4 hours in a pH 4.6 bufferand 85.4% after 12 hours in a pH 6.8 buffer. These results prove thesuitability of the formulation for an extended release profile.

Comparative Example 108

40.2 g of Phosal 50 PG, 4.7 g of polysorbate 80, 2.3 g of purifiedwater, 2.3 g of Ethanol, anhydrous, 2.7 g of colloidal anhydrous silica,and 7.8 g of pseudoephedrine HCl were mixed to obtain a yellow gel thatwas homogenous, soft, flowable, pourable, and almost clear.

Comparative Example 109

38.9 g of Phosal 50 PG, 4.7 g of polysorbate 80, 2.3 g of purifiedwater, 2.3 g of Ethanol, anhydrous, 4.0 g of colloidal anhydrous silica,and 7.8 g of pseudoephedrine HCl were mixed to obtain a yellow gel thatwas homogenous, soft, flowable, pourable, and almost clear.

Comparative Example 110

37.6 g of Phosal 50 PG, 12.7 g of caprylocaproyl macrogol-8 glycerides,2.7 g of purified water, 2.7 g of xanthan gum, and 7.8 g ofpseudoephedrine HCl were mixed to obtain a yellow gel that washomogenous, soft, flowable, pourable, and was turbid.

Comparative Example 111

37.6 g of Phosal 50 PG, 12.7 g of caprylocaproyl macrogol-8 glycerides,2.7 g of purified water, 2.7 g of xanthan gum, and 7.8 g ofpseudoephedrine HCl were mixed to obtain a yellow gel that washomogenous, soft, flowable, pourable, and turbid.

Comparative Example 112

37.6 g of Phosal 50 PG, 12.7 g of caprylocaproyl macrogol-8 glycerides,2.7 g of purified water, 2.7 g of xanthan gum, and 7.8 g ofpseudoephedrine HCl were mixed to obtain a yellow gel that washomogenous, soft, flowable, pourable, and turbid.

Comparative Example 113

36.9 g of Phosal 50 PG, 12.7 g of caprylocaproyl macrogol-8 glycerides,3.3 g of purified water, 2.7 g of xanthan gum, and 7.8 g ofpseudoephedrine HCl were mixed to obtain a yellow gel that washomogenous, soft, flowable, pourable, and turbid.

Comparative Example 114

36.4 g of Phosal 50 PG, 12.7 g of caprylocaproyl macrogol-8 glycerides,3.8 g of purified water, 2.7 g of xanthan gum, and 7.8 g ofpseudoephedrine HCl were mixed to obtain a yellow gel that washomogenous, soft, flowable, pourable, and turbid.

Comparative Example 115

36.4 g of Phosal 50 PG, 12.7 g of caprylocaproyl macrogol-8 glycerides,3.8 g of purified water, 2.7 g of xanthan gum, and 7.8 g ofpseudoephedrine HCl were mixed to obtain a yellow gel that washomogenous, soft, flowable, pourable, and turbid.

Working Example 116

35.8 g of Phosal 50 PG, 12.7 g of caprylocaproyl macrogol-8 glycerides,4.4 g of purified water, 2.7 g of xanthan gum, and 7.8 g ofpseudoephedrine HCl were mixed to obtain a yellow gel that washomogenous, soft, flowable, pourable, and turbid. After treatment withhot water, 3.8% pseudoephedrine HCl was detected in the mixture drawninto a syringe. After a 12 hour dissolution treatment (2 hours in 0.1NHCl, 2 hours in a pH 4.6 buffer, and 8 hours in a pH 6.8 buffer) thefollowing percentages of the active substance was detected in thedissolution media: 35.1% in 0.1 N HCl after 120 min, and 54.2% in a pH4.6 buffer after 4 hours. 95.5% of the pseudoephedrine HCl was releasedafter 12 hours in a pH 6.8 buffer from 950 mg of fill.

Working Example 117

35.8 g of Phosal 50 PG, 12.7 g of caprylocaproyl macrogol-8 glycerides,4.4 g of purified water, 2.7 g of xanthan gum, and 7.8 g ofpseudoephedrine HCl were mixed to obtain a yellow gel that washomogenous, soft, flowable, pourable, and turbid. After a treatment withhot water, 4.4% pseudoephedrine HCl was detected in the mixture drawninto a syringe. The dissolution profile of the active substance from labfilled capsules was tested over 12 hours (2 hours in 0.1 N HCl, 2 hoursin a pH 4.6 buffer and 8 hours in a pH 6.8 buffer). 47.4% ofpseudoephedrine HCl was released after 2 hours in 0.1N HCl from labfilled softgels containing 116.48 mg pseudoephedrine HCl in 950 mg offill suspension. After a further 2 hours in a pH 4.6 buffer 70.9% of theactive substance was detected. 95.4% of oxycodone HCl was calculated tobe released after 12 hours in a pH 6.8 buffer. These data demonstratethe suitability of formulations of Examples 116 and 117 to obtain a 12hour extended release profile.

Examples 118 to 126: Macrogol/Labrasol Pseudoephedrine Formulations

Based on the immediate release xanthan gum formulation A the dosagelevel of xanthan gum was increased to 20 mg (2.1%) in the composition ofExample 123, and 40 mg (7%) in the composition of Example 126.

Additionally two formulations (Example Nos. 118 and 119) with 85.00 mg(9.4%) xanthan gum without glycerol and water in the fill were testedfor syringeability and dissolution in 0.1 N HCl over 120 and 300minutes. The dissolution profiles over 120 min in 0.1 N HCl or 300 minin 0.1 N HCl, buffer pH 4.6 and 6.8 show, that by increasing the xanthangum or colloidal anhydrous silica concentration the release profile wasnot extended. The syringeability profile appeared to be compliant (up to12.1%).

Working Example 118

54.4 g of macrogol 600, 8.8 g of caprylocaproyl macrogol-8 glycerides,2.4 g of anhydrous glycerol, 0.6 g of purified water, 2.5 g of colloidalanhydrous silica, 0.3 g of xanthan gum, and 5.8 g of pseudoephedrine HClwere mixed to obtain an off-white suspension that was pourable,flowable, spatters on boiling, with little foam, and formed a gel. Itcould hardly be drawn up into the syringe. 15.2% of pseudoephedrine HClwas detected. 100% of pseudoephedrine HCl was released within 30 minutesin 0.1 N HCl from capsules containing 116.48 mg pseudoephedrine HCl in a940 mg of fill suspension.

Working Example 119

34.1 g of macrogol 400, 11.3 g of caprylocaproyl macrogol-8 glycerides,5.7 g of xanthan gum, 1.1 g of colloidal anhydrous silica, and 7.8 g ofpseudoephedrine HCl were mixed to obtain an off-white suspension thatwas pourable, thin, sedimented, that spatters on boiling, forming littlefoam, but formed a strong gel. This gel could not be drawn up into asyringe; no pseudoephedrine HCl was detected in the syringe afterboiling of 940 mg suspension with 5 ml water. 71.2% of pseudoephedrineHCl was released within 30 minutes in 0.1 N HCl from lab filled capsulescontaining 116.48 mg pseudoephedrine HCl in 940 mg of fill suspension.

Working Example 120

34.1 g of macrogol 400, 11.3 g of macrogolglycerolhydroxystearate 40,5.7 g of xanthan gum, 1.1 g of colloidal anhydrous silica, and 7.8 g ofpseudoephedrine HCl were mixed to obtain an off-white suspension thatwas pourable, flowable, that spatters on boiling, forming little foam,but a gel formed. It could hardly be drawn up into the syringe; 0.7% ofpseudoephedrine HCl was detected in the syringe after boiling of 940 mgof suspension with 5 mL of water. 84.9% of pseudoephedrine HCl wasreleased within 30 minutes in 0.1 N HCl from lab filled capsulescontaining 116.48 mg pseudoephedrine HCl in 900 mg of fill suspension.

Working Example 121

54.5 g of macrogol 600, 8.8 g of caprylocaproyl macrogol-8 glycerides,2.4 g of anhydrous glycerol, 0.6 g of purified water, 2.5 g of colloidalanhydrous silica, 0.2 g of xanthan gum, 5.8 g of pseudoephedrine HClwere mixed to obtain an off-white suspension that was pourable, thin,sedimented, that spatters on boiling, forming little foam, but formed agel. It could not be drawn up into the syringe.

Working Example 122

54.6 g of macrogol 600, 8.8 g of caprylocaproyl macrogol-8 glycerides,2.4 g of anhydrous glycerol, 0.6 g of purified water, 2.5 g of colloidalanhydrous silica, 0.2 g of xanthan gum, 5.8 g of pseudoephedrine HClwere mixed to obtain an off-white suspension that was pourable,flowable, that spatters on boiling, forming little foam, but formed agel. It could not be drawn up into the syringe.

Working Example 123

52.9 g of macrogol 600, 8.8 g of caprylocaproyl macrogol-8 glycerides,2.4 g of anhydrous glycerol, 0.6 g of purified water, 2.5 g of colloidalanhydrous silica, 1.0 g of xanthan gum, 5.8 g of pseudoephedrine HClwere mixed to obtain an off-white suspension that was pourable,flowable, spatters on boiling, forming little foam, but formed a gel. Itcould hardly be drawn up into the syringe.

Working Example 124

51.4 g of macrogol 600, 8.3 g of caprylocaproyl macrogol-8 glycerides,2.4 g of anhydrous glycerol, 0.6 g of purified water, 4.5 g of colloidalanhydrous silica, 0.3 g of xanthan gum, 5.8 g of pseudoephedrine HClwere mixed to obtain an off-white suspension that was pourable,flowable, spatters on boiling, forming little foam, but formed a gel. Itcould hardly be drawn up into the syringe.

Comparative Example 125

27.1 g of macrogol 600, 27.0 g of Kollisolv P 124 (Lutrol F44), 8.8 g ofcaprylocaproyl macrogol-8 glycerides, 2.4 g of anhydrous glycerol, 0.6 gof purified water, 2.5 g of colloidal anhydrous silica, 4.0 g of xanthangum, 5.8 g of pseudoephedrine HCl were mixed to obtain an off-whitesuspension that was pourable and flowable.

Working Example 126

79.8 g of macrogol 600, 25.5 g of caprylocaproyl macrogol-8 glycerides,and 7.8 g of anhydrous glycerol, 10.8 g of purified water, 8.3 g ofcolloidal anhydrous silica, 6.7 g of xanthan gum (Xanthural 180), 19.4 gof pseudoephedrine HCl were mixed to obtain an off-white suspension thatwas pourable, flowable, and exhibits sedimentation. 2.1% ofpseudoephedrine HCl was detected in the syringe after boiling of 950 mgof the suspension with 5 ml water. 81.2% of the pseudoephedrine HCl wasreleased within 30 minutes in 0.1 N HCl from lab filled capsulescontaining 116.48 mg pseudoephedrine HCl in 950 mg of fill suspension.

Examples 127-135 Additional Hydrophilic Pseudoephedrine FormulationsWorking Example 127

45.9 g of macrogol 600, 8.0 g of caprylocaproyl macrogol-8 glycerides,2.4 g of anhydrous glycerol, 0.6 g of purified water, 3.3 g of colloidalanhydrous silica, 4.0 g of Amberlite IRP64, 5.8 g of pseudoephedrine HClwere mixed to obtain an off-white suspension that was pourable andflowable. 8.0% of pseudoephedrine HCl was detected in the syringe afterboiling with 5 mL water. 97% of the pseudoephedrine HCl was releasedwithin 30 minutes in 0.1 N HCl from lab filled capsules containing116.48 mg pseudoephedrine HCl in 940 mg of fill suspension.

Working Example 128

30.6 g of macrogol 600, 10.7 g of caprylocaproyl macrogol-8 glycerides,3.1 g of anhydrous glycerol, 0.8 g of purified water, 4.3 g of colloidalanhydrous silica, 5.3 g of Amberlite IRP69, and 7.8 g of pseudoephedrineHCl were mixed to obtain a brownish suspension that was pourable,flowable, and exhibited sedimentation. 5.5% of pseudoephedrine HCl wasdetected in the syringe after boiling with 5 ml water. 91.5% ofpseudoephedrine HCl was released within 30 minutes in 0.1 N HCl from labfilled capsules containing 116.48 mg pseudoephedrine HCl in 940 mg offill suspension.

Working Example 129

30.6 g of macrogol 600, 10.7 g of caprylocaproyl macrogol-8 glycerides,3.1 g of anhydrous glycerol, 0.8 g of purified water, 4.3 g of colloidalanhydrous silica, 5.3 g of Duolite AP143/1093, and 7.8 g ofpseudoephedrine HCl were mixed to obtain an off-white suspension thatwas pourable and flowable. 11.0% of pseudoephedrine HCl was detected inthe syringe after boiling with 5 mL of water. 95.6% of pseudoephedrineHCl was released within 30 minutes in 0.1 N HCl from lab filled capsulescontaining 116.48 mg pseudoephedrine HCl in 940 mg of fill suspension.

Comparative Example 130

30.6 g of macrogol 600, 10.7 g of caprylocaproyl macrogol-8 glycerides,3.1 g of anhydrous glycerol, 0.8 g of purified water, 4.3 g of colloidalanhydrous silica, 5.3 g of Amberlite IRP69, and 7.8 g of pseudoephedrineHCl were mixed to obtain a brownish suspension that was pourable,flowable, and exhibited sedimentation.

Comparative Example 131

30.6 g of macrogol 600, 10.7 g of caprylocaproyl macrogol-8 glycerides,3.1 g of anhydrous glycerol, 0.8 g of purified water, 4.3 g of colloidalanhydrous silica, 5.3 g of Duolite AP143/1093, and 7.8 g ofpseudoephedrine HCl were mixed to obtain an off-white suspension thatwas viscous, pourable, and flowable.

Comparative Example 132

77.8 g of macrogol 600, 28.0 g of caprylocaproyl macrogol-8 glycerides,9.4 g of anhydrous glycerol, 2.5 g of purified water, 9.0 g of colloidalanhydrous silica, 38.0 g of Amberlite IRP69, and 23.3 g ofpseudoephedrine HCl were mixed to obtain a brownish suspension that wasviscous, pourable, and flowable.

Comparative Example 133

77.8 g of macrogol 600, 28.0 g of caprylocaproyl macrogol-8 glycerides,9.4 g of anhydrous glycerol, 2.5 g of purified water, 9.0 g of colloidalanhydrous silica, 38.0 g of Duolite AP143/1093, and 23.3 g ofpseudoephedrine HCl were mixed to obtain an off-white suspension thatwas viscous, pourable, and flowable.

Working Example 134

79.8 g of macrogol 600, 26.7 g of caprylocaproyl macrogol-8 glycerides,7.8 g of anhydrous glycerol, 2.1 g of purified water, 14.2 g ofcolloidal anhydrous silica, 6.7 g of Amberlite IRP69, and 19.4 g ofpseudoephedrine HCl were mixed to obtain a brownish suspension that wasviscous, pourable, and flowable. 10.2% of pseudoephedrine HCl wasdetected in the syringe. 93.4% of the pseudoephedrine HCl was releasedwithin 30 minutes in 0.1 N HCl from lab filled capsules containing116.48 mg pseudoephedrine HCl in 940 mg of fill suspension.

Working Example 135

76.5 g of macrogol 600, 26.7 g of caprylocaproyl macrogol-8 glycerides,7.8 g of anhydrous glycerol, 2.1 g of purified water, 10.8 g ofcolloidal anhydrous silica, 13.3 g of Duolite AP143/1093, and 19.4 g ofpseudoephedrine HCl were mixed to obtain a brownish suspension that wasviscous, pourable, and flowable. The liquid was bubbling under intenseincrease of viscosity at boiling with water. A thickened stable foamresulted, that could hardly be drawn up into a syringe. 12.1% ofpseudoephedrine HCl was detected in the syringe. 96.9% ofpseudoephedrine HCl was released within 30 minutes in 0.1 N HCl from labfilled capsules containing 116.48 mg pseudoephedrine HCl in 940 mg offill suspension.

Working Example 136

76.5 g of macrogol 600, 26.7 g of caprylocaproyl macrogol-8 glycerides,7.8 g of anhydrous glycerol, 2.1 g of purified water, 10.8 g ofcolloidal anhydrous silica, 13.3 g of Amberlite IRP88, and 19.4 g ofpseudoephedrine HCl were mixed to obtain an off-white suspension thatwas viscous, pourable, and flowable. Upon boiling with water, anincrease of the viscosity and foaming was exhibited. 3.4% ofpseudoephedrine HCl was detected in the syringe. 95.2% ofpseudoephedrine HCl was released within 30 minutes in 0.1 N HCl from labfilled capsules containing 116.48 mg pseudoephedrine HCl in 940 mg offill suspension.

Examples 137 to 141: Immediate and Extended Release Oxycodone HClFormulations

The compositions of Example Nos. 137 (comprising xanthan gum) and 139(comprising Amberlite IRP64) fulfill the specifications for an immediaterelease profile. (>80% within 30 minutes). The use of Amberlite IRP69and Duolite AP 143 in combination with the increased concentration of8.5% colloidal anhydrous silica leads to a delayed dissolution profile.Within 30 minutes only 52.3% (Amberlite IRP69) or 56.5% (DuoliteAP143/1093) are released. After 60 minutes 91.4% (Amberlite IRP69) or99.7% (Duolite AP143/1093) of oxycodone HCl have be released.

Selected compositions of the Examples below were tested forsyringeability and abuse resistance. A maximum of 17.6% of the API wasdetected in the syringe after boiling of the capsule fill with 5 mLwater and filtration through a cigarette filter. The compositions ofExample Nos. 140, 139, 137, and 138 showed residual levels of 12.4,17.6, 2.6 and 4.0%, respectively, of the active pharmaceuticalingredient oxycodone in the residue after boiling and filtering themixture.

The injectability of oxycodone HCl from all four abuse deterrentformulation types was significantly reduced, especially for theAmberlite IRP69 and Duolite formulations when used in combination withincreased amounts of colloidal anhydrous silica, which showed a delayedoxycodone release after 60 minutes. By reducing the concentration ofcolloidal anhydrous silica to 6.9%, an immediate release dissolutionprofile with more than 93% of oxycodone HCl released within 30 minutesin 0.1 N HCl was obtained. At least one of the formulations belowappears to meet the extended release profile requirements.

Working Example 137

27.3 g of macrogol 600, 18.1 g of caprylocaproyl macrogol-8 glycerides,2.5 g of anhydrous glycerol, 0.7 g of purified water, 4.0 g of colloidalanhydrous silica, 2.0 g of Amberlite IRP69, and 2.0 g of oxycodone HClwere mixed to obtain a brownish suspension. After boiling of 470 mg offill with 5 mL water, slight foaming with a viscosity increase wasobserved. 8.6% of oxycodone HCl was detected in the syringe. 93% ofoxycodone HCl was released within 30 minutes in 0.1 N HCl from labfilled capsules containing 20.00 mg oxycodone HCl in 470 mg of fillsuspension.

Working Example 138

25.3 g of macrogol 600, 8.5 g of caprylocaproyl macrogol-8 glycerides,2.5 g of anhydrous glycerol, 0.7 g of purified water, 4.0 g of colloidalanhydrous silica, 4.0 g of Duolite AP143/1093, and 2.0 g of oxycodoneHCl were mixed to obtain an off-white suspension. The liquid bubbledwith an intense increase of viscosity upon boiling with water. Duringboiling of the liquid with 5 mL of water, a thickening stable foamresulted which could hardly be drawn up into a syringe. 14.1% ofoxycodone HCl was detected in the syringe. 95.6% of the oxycodone HClwas released within 30 minutes in 0.1 N HCl from lab filled capsulescontaining 20.00 mg oxycodone HCl in 470 mg of fill suspension.

Working Example 139

25.3 g of macrogol 600, 8.5 g of caprylocaproyl macrogol-8 glycerides,2.5 g of anhydrous glycerol, 0.7 g of purified water, 4.0 g of colloidalanhydrous silica, 4.0 g of Amberlite IRP64, and 2.0 g of oxycodone HClwere mixed to obtain an off-white suspension. Upon heating of 470 mgsuspension with 5 mL water, a slight viscosity increase and frothingwere observed. 18.9% oxycodone HCl has been detected in the syringe.91.1% of oxycodone HCl was released within 30 minutes in 0.1 N HCl fromlab filled capsules containing 20.00 mg oxycodone HCl in 470 mg of fillsuspension.

Working Example 140

29.5 g of macrogol 600, 9.0 g of caprylocaproyl macrogol-8 glycerides,2.5 g of anhydrous glycerol, 0.7 g of purified water, 4.0 g of colloidalanhydrous silica, 0.3 g of xanthan gum, and 2.0 g of oxycodone HCl weremixed to obtain an off-white suspension. Upon heating 480 mg of thesuspension with 5 mL water, an intense increase of viscosity with slightfoaming was observed. 12.5% of oxycodone HCl was detected in thesyringe. 98.8% of oxycodone HCl was released within 30 minutes in 0.1 NHCl from lab filled capsules containing 20.00 mg oxycodone HCl in 470 mgof fill suspension.

Working Example 141

38.2 g of Phosal 50 PG, 12.7 g of caprylocaproyl macrogol-8 glycerides,4.4 g of purified water, 2.7 g of xanthan gum, and 5.3 g of oxycodoneHCl were mixed to obtain a yellow gel. An intense viscosity increase andstable frothing was observed upon heating of 950 mg of the gel withwater. 7.5% of oxycodone HCl was detected in the syringe. Thedissolution profile of the active substance from lab filled capsules wastested over 12 hours (2 hours in 0.1 N HCl, 2 hours in a pH 4.6 bufferand 8 hours in a pH 6.8 buffer). 33.6% of oxycodone HCl was releasedafter 2 hours in 0.1N HCl from lab filled softgels containing 80 mgoxycodone HCl in 950 mg of fill suspension. After further 2 hours in apH 4.6 buffer, 45.2% of the active substance was detected. 88.4% ofoxycodone HCl was calculated to have been released after 12 hours in apH 6.8 buffer. These data show the suitability of the formulation forproviding an extended release profile over 12 hours.

Examples 142 to 146: Codeine Phosphate Formulations

Example Nos. 142 to 146 are directed to immediate release and extendedrelease codeine phosphate formulations. One of the formulations belowappears to meet the extended release profile requirements.

Working Example 142

26.3 g of macrogol 600, 8.5 g of caprylocaproyl macrogol-8 glycerides,2.5 g of anhydrous glycerol, 0.7 g of purified water, 4.0 g of colloidalanhydrous silica, 2.0 g of Amberlite IRP69, and 3.0 g of codeinephosphate, hemihydrate were mixed to obtain a brownish suspension. 9.5%codeine phosphate was detected in the syringe after boiling of 470 mgsuspension with 5 mL of water. 95.9% of codeine phosphate was releasedwithin 30 minutes in 0.1 N HCl from lab filled capsules containing 30.00mg codeine phosphate, hemihydrate in a 470 mg of fill suspension.

Working Example 143

24.3 g of macrogol 600, 8.5 g of caprylocaproyl macrogol-8 glycerides,2.5 g of anhydrous glycerol, 0.7 g of purified water, 4.0 g of colloidalanhydrous silica, 4.0 g of Duolite AP143/1093, and 3.0 g of codeinephosphate hemihydrate were mixed to obtain an off-white suspension.97.3% of codeine phosphate was released within 30 minutes in 0.1 N HClfrom lab filled capsules containing 30.00 mg codeine phosphate,hemihydrate in 470 mg of fill suspension.

Working Example 144

24.3 g of macrogol 600, 8.5 g of caprylocaproyl macrogol-8 glycerides,2.5 g of anhydrous glycerol, 0.7 g of purified water, 4.0 g of colloidalanhydrous silica, 4.0 g of Amberlite IRP64, and 3.0 g of codeinephosphate hemihydrate were mixed to obtain an off white suspension.11.9% of codeine phosphate was detected in a syringe after boiling of470 mg suspension with 5 mL water. 99.0% of codeine phosphate wasreleased within 30 minutes in 0.1 N HCl from lab filled capsulescontaining 30.00 mg codeine phosphate hemihydrate in a 470 mg of fillsuspension.

Working Example 145

28.5 g of macrogol 600, 9.0 g of caprylocaproyl macrogol-8 glycerides,2.5 g of anhydrous glycerol, 0.7 g of purified water, 3.0 g of colloidalanhydrous silica, 0.3 g of xanthan gum, 3.0 g of codeine phosphatehemihydrate were mixed to obtain an off-white suspension. 9.0% ofcodeine phosphate was detected in a syringe after boiling of 480 mgsuspension with 5 mL water. 98.8% of codeine phosphate was releasedwithin 30 minutes in 0.1 N HCl from lab filled capsules containing 30.00mg codeine phosphate hemihydrate in a 480 mg of fill suspension.

Working Example 146

39.6 g of Phosal 50 PG, 12.7 g of caprylocaproyl macrogol-8 glycerides,4.4 g of purified water, 2.7 g of xanthan gum, 3.3 g of codeinephosphate, hemihydrate were mixed to obtain a yellow gel. 3.8% ofcodeine phosphate was detected in a syringe after boiling with 5 mLwater. The dissolution profile of the active substance from lab filledcapsules was tested over 12 hours (2 hours in 0.1 N HCl, 2 hours in a pH4.6 buffer and 8 hours in a pH 6.8 buffer). 25.1% of codeine phosphate,hemihydrate was released after 2 hours in 0.1 N HCl from lab filledsoftgels containing 50 mg codeine phosphate hemihydrate in 950 mg offill suspension. After further 2 hours in a pH 4.6 buffer, 44.7% of theactive substance was detected. 86.5% of codeine phosphate hemihydratewas calculated to be released within 12 hours in a pH 6.8 buffer. Thisexample demonstrates the suitability of the formulation for providing anextended release profile over 12 hours.

Examples 147 to 157: Immediate and Extended Release Tilidine HClFormulations

Example Nos. 147 to 157 are directed to immediate release and extendedrelease Tilidine HCl formulations. One of the formulations below appearsto meet the extended release profile requirements.

Working Example 147

32.8 g of macrogol 600, 11.3 g of caprylocaproyl macrogol-8 glycerides,3.1 g of anhydrous glycerol, 0.8 g of purified water, 5.0 g of colloidalanhydrous silica, 2.7 g of Amberlite IRP69, and 6.9 g of tilidinehydrochloride hemihydrate were mixed to obtain a brownish suspensionthat was viscous, pourable and flowable. Boiling of 940 mg of thissuspension with 5 mL water yielded a mixture that bubbled slightly, andexhibited a viscosity increase. 8.9% of tilidine HCl was detected in thesyringe. 96.9% tilidine HCl was released from lab filled softgelscontaining 100 mg of tilidine HCl in a 940 mg of fill suspension within30 minutes in 0.1 N HCl.

Working Example 148

31.5 g of macrogol 600, 10.7 g of caprylocaproyl macrogol-8 glycerides,3.1 g of anhydrous glycerol, 0.8 g of purified water, 4.3 g of colloidalanhydrous silica, 5.3 g of Duolite AP143/1093, 6.9 g of tilidinehydrochloride hemihydrate were mixed to obtain a brownish suspensionthat was viscous, pourable and flowable. Boiling of 940 mg of thissuspension with 5 mL water yielded a mixture that bubbled and exhibiteda high viscosity increase. A thick, stable foam resulted, which couldhardly be drawn up into a syringe. 6.5% of tilidine HCl was detected inthe syringe. 100.3% was detected as released from lab filled softgelscontaining 100 mg tilidine hydrochloride hemihydrate in 940 mg of fillsuspension within 30 minutes in 0.1 N HCl.

Working Example 149

15.8 g of macrogol 600, 5.3 g of caprylocaproyl macrogol-8 glycerides,1.6 g of anhydrous glycerol, 0.4 g of purified water, 2.2 g of colloidalanhydrous silica, 2.7 g of Amberlite IRP64, 3.4 g of tilidinehydrochloride hemihydrate were mixed to obtain an off-white suspension.Boiling of 470 mg of this suspension with 5 mL water yielded a mixturethat bubbled slightly, and exhibited a viscosity increase. 2.5% oftilidine HCl was detected in a syringe after boiling with a reducedamount of 2.5 mL of water. 15.2% of tilidine HCl was detected in asyringe after boiling with 5 mL of water. 97.0% of tilidine HCl wasreleased from lab filled softgels containing 50 mg tilidine HCl in a 470mg of fill suspension within 30 minutes in 0.1 N HCl.

Working Example 150

31.5 g of macrogol 600, 10.7 g of caprylocaproyl macrogol-8 glycerides,3.1 g of anhydrous glycerol, 0.8 g of purified water, 4.3 g of colloidalanhydrous silica, 5.3 g of Amberlite IRP64, 6.9 g of tilidinehydrochloride hemihydrate were mixed to obtain an off-white suspension.Boiling this suspension with 5 mL water yielded a mixture that bubbledslightly, and exhibited a viscosity increase. 6.6% of tilidine HCl wasdetected in a syringe after boiling with 5 mL of water. 99.9% oftilidine HCl was released from lab filled softgels containing 100 mgtilidine HCl in a 940 mg of fill suspension within 30 minutes in 0.1 NHCl.

Working Example 151

7.9 g of macrogol 600, 2.7 g of caprylocaproyl macrogol-8 glycerides,0.8 g of anhydrous glycerol, 0.8 g of purified water, 1.1 g of colloidalanhydrous silica, 1.3 g of Amberlite IRP64, 1.7 g of tilidinehydrochloride hemihydrate were mixed to obtain an off-white suspension.Boiling of 180 mg of this suspension (corresponding to 20 mg of tilidineHCl) with water yielded a mixture that bubbled slightly, and exhibited aviscosity increase. 13.0% of tilidine HCl was detected in a syringeafter boiling with a reduced amount of 2.5 mL of water. 41.4% oftilidine HCl was detected in a syringe after boiling with 5 mL of water.This behavior shows that amounts above a minimum total concentration ofthe ion exchange resin could be used to achieve abuse resistantproperties of the fill.

Working Example 152

16.9 g of macrogol 600, 5.7 g of caprylocaproyl macrogol-8 glycerides,1.7 g of anhydrous glycerol, 0.4 g of purified water, 2.7 g of colloidalanhydrous silica, 2.7 g of Amberlite IRP64, 1.4 g of tilidinehydrochloride hemihydrate were mixed to obtain an off-white suspension.Boiling of 470 mg of this suspension with 5 mL of water yielded amixture that bubbled slightly, and exhibited a viscosity increase. 8.9%of tilidine HCl was detected in a syringe. 99.3% of tilidine HCl wasreleased from lab filled softgels containing 50 mg tilidine HCl in a 470mg of fill suspension within 30 minutes in 0.1 N HCl.

Working Example 153

37.2 g of macrogol 600, 11.7 g of caprylocaproyl macrogol-8 glycerides,3.1 g of anhydrous glycerol, 0.8 g of purified water, 3.3 g of colloidalanhydrous silica, 0.3 g of xanthan gum, 6.9 g of tilidine hydrochloridehemihydrate were mixed to obtain an off-white suspension. Heating of 940mg of the fill suspension with 5 mL of water showed an intense increaseof viscosity with slight foaming. 3.9% of tilidine HCl was detected in asyringe. 96.9% of the tilidine hydrochloride hemihydrate was releasedfrom lab filled softgels containing 100 mg tilidine hydrochloridehemihydrate in 950 mg of fill suspension within 30 minutes in 0.1 N HCl.

Working Example 154

18.6 g of macrogol 600, 5.8 g of caprylocaproyl macrogol-8 glycerides,2.4 g of anhydrous glycerol, 0.4 g of purified water, 1.6 g of colloidalanhydrous silica, 0.2 g of xanthan gum, 3.4 g of tilidine hydrochloridehemihydrate were mixed to obtain an off-white suspension. Heating withwater results in an intense increase of viscosity with slight foaming.0.4% of tilidine hydrochloride hemihydrate was detected in a syringeafter boiling of 470 mg of fill suspension (corresponding to 50 mgtilidine HCl) with a reduced amount of 2.5 mL water. 11.0% of tilidinehydrochloride hemihydrate was detected in the syringe after boiling of470 mg of fill suspension (corresponding to 50 mg tilidine HCl) with 5mL water. 96.2% tilidine hydrochloride hemihydrate was released from labfilled softgels containing 50 mg tilidine hydrochloride hemihydrate in470 mg of fill suspension within 30 minutes in 0.1 N HCl.

Working Example 155

7.4 g of macrogol 600, 2.3 g of caprylocaproyl macrogol-8 glycerides,0.6 g of anhydrous glycerol, 0.2 g of purified water, 0.7 g of colloidalanhydrous silica, 0.1 g of xanthan gum, 1.4 g of tilidine hydrochloridehemihydrate were mixed to obtain an off-white suspension. Upon heatingwith water, an intense increase of viscosity with slight foaming wasobserved. 5.8% of tilidine HCl was detected in a syringe after boilingof 190 mg of fill suspension (corresponding to 20 mg tilidine HCl) witha reduced amount of 2.5 mL water. 38.2% of tilidine HCl was detected inthe syringe after boiling of 190 mg of fill suspension (corresponding to20 mg tilidine HCl) with 5 mL water. These results demonstrate that useof an amount of xanthan gum above a minimum total concentration ofxanthan gum provided abuse resistant properties to the capsule fill.

Working Example 156

19.7 g of macrogol 600, 6.0 g of caprylocaproyl macrogol-8 glycerides,1.7 g of anhydrous glycerol, 0.4 g of purified water, 2.0 g of colloidalanhydrous silica, 0.2 g of xanthan gum, 1.4 g of tilidine hydrochloridehemihydrate were mixed to obtain an off-white suspension. Upon heatingof 470 mg of fill suspension with 5 mL water an intense increase ofviscosity with slight foaming was observed. 9.6% tilidine HCl wasdetected in a syringe. 100.5% of tilidine hydrochloride hemihydrate wascalculated to be released from lab filled softgels containing 50 mgtilidine hydrochloride hemihydrate in 470 mg of fill suspension within30 minutes in 0.1 N HCl.

Working Example 157

36.0 g of Phosal 50 PG, 12.7 g of caprylocaproyl macrogol-8 glycerides,4.4 g of purified water, 2.7 g of xanthan gum and 6.9 g of tilidinehydrochloride hemihydrate were mixed to obtain a yellow gel. An intenseviscosity increase and stable frothing was observed at heating of 940 mgof the yellow gel with water. 2.9% of tilidine hydrochloride hemihydratewas detected in a syringe. The dissolution profile of the activesubstance from lab filled capsules was tested over 12 hours (2 hours in0.1 N HCl, 2 hours in a pH 4.6 buffer and 8 hours in a pH 6.8 buffer).42.7% of tilidine hydrochloride hemihydrate was released after 2 hoursin 0.1N HCl from lab filled softgels containing 100 mg tilidine HCl in940 mg of fill suspension. After further 2 hours in a pH 4.6 buffer,57.1% of the active substance was detected. 85.7% of tilidinehydrochloride was calculated to be released after 12 hours in a pH 6.8buffer. These data shows the suitability of the formulation forproviding an extended release profile over 12 hours.

The invention claimed is:
 1. An immediate release parenteral abuse resistant capsule comprising a shell encapsulating a parenteral abuse resistant liquid, comprising: (a) an abuse-susceptible active pharmaceutical ingredient selected from the group consisting of opiates, opioids, tranquilizers, stimulants and narcotics; (b) at least 40 wt. % of a hydrophilic carrier selected from one or more of macrogol 400, macrogol 600, and macrogol 1500, and optionally one or more of propylene glycol, glycerol, and water, to dissolve or suspend the active pharmaceutical ingredient; (c) a surfactant selected from a macrogolglycerol ricinoleate, sorbitol monolaurate, macrogolglycerol hydroxystearate and caprylocaproylmacrogol-8-glycerides; (d) 1-10 wt. % of colloidal anhydrous silica; and (e) 0.2-0.6 wt. % of a viscosity enhancer selected from the group consisting of gums of acacia, pectin, agar, tragacanth, guar, xanthan, locust bean, tara, karaya, gellan, welan, and rhamsan; such that a mixture of about 250 to about 1000 milligrams of the abuse resistant liquid with 5 milliliters of water at the mixture's boiling point forms a viscous phase, wherein about 33% or less of the pharmaceutically active ingredient can be recovered from the viscous phase drawn up into a 25 millimeter needle having an inner diameter of 0.60 millimeters and wherein all weight percentages being based on a weight of the parenteral abuse resistant liquid, wherein the capsule releases more than 80% of the active pharmaceutical ingredient within the gastrointestinal tract within 30 minutes of administration.
 2. The parenteral abuse resistant capsule of claim 1, wherein the viscous phase cannot pass through a 25 millimeter needle having an inner diameter of 0.60 millimeters.
 3. The parenteral abuse resistant capsule of claim 1, wherein the viscosity enhancer is xanthan gum.
 4. The parenteral abuse resistant capsule of claim 1 comprising caprylocaproylmacrogol-8 glycerides, and further comprising water and glycerol.
 5. The parenteral abuse resistant capsule of claim 1 comprising caprylocaproyl macrogol-8 glycerides and further comprising phosphatidylcholine and propylene glycol.
 6. The parenteral abuse resistant capsule of claim 1 comprising (i) 40 to 60 wt % macrogol 600; (ii) 15 to 25 wt % caprylocaproylmacrogol-8 glycerides; (iii) 3 to 10 wt % colloidal anhydrous silica; (iv) 0.2 to 0.6 wt % xanthan gum; and further comprising (v) 3 to 6 wt % glycerol; and (vi) 0.5 to 10 wt % water wherein the weight percentages are calculated with respect to the weight of the parenteral abuse resistant liquid.
 7. The parenteral abuse resistant capsule of claim 1, wherein the active pharmaceutical ingredient is selected from the group consisting of N-{1-[2-(4-ethyl-5-oxo-2-tetrazolin-1-yl)ethyl]-4-methoxymethyl-4-piperidyl}propionanilide; alfentanil; 5,5-diallylbarbituric acid; allobarbital; allylprodine; alphaprodine; 8-chloro-1-methyl-6-phenyl-4H-[1,2,4]triazolo[4,3-a][1,4]-benzodiazepine; alprazolam; 2-diethylaminopropiophenone; amfepramone, (+)-αmethylphenethylamine; amphetamine; 2-(α-methylphenethylamino)-2-phenylacetonitrile; amphetaminil; 5-ethyl-5-isopentylbarbituric acid; amobarbital; anileridine; apocodeine; 5,5-diethylbarbituric acid; barbital; benzylmorphine; bezitramide; 7-bromo-5-(2-pyridyl)-1H-1,4-benzodiazepine-2(3H)-one; bromazepam; 2-bromo-4-(2-chlorophenyl)-9-methyl-1-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine; brotizolam, 17-cyclopropylmethyl-4,5a-epoxy-7a[(S)-1-hydroxy-1,2,2-trimethyl-propyl]-6-methoxy-6,14-endo-ethanomorphinan-3-ol; buprenorphine; 5-butyl-5-ethylbarbituric acid; butobarbital; butorphanol; (7-chloro-1,3-dihydro-1-methyl-2-oxo-5-phenyl-2H-1,4-benzodiazepin-3-yl)dimethylcarbamate; camazepam; (1S,2S)-2-amino-1-phenyl-1-propanol; cathine; d-norpseudoephedrine; 7-chloro-N-methyl-5-phenyl-3H-1,4-benzodiazepin-2-yl-amine 4-oxide; chlordiazepoxide, 7-chloro-1-methyl-5-phenyl-1H-1,5-benzodiazepine-2,4(3H,5H)-dione; clobazam, 5-(2-chlorophenyl)-7-nitro-1H-1,4-benzodiazepin-2(3H)-one; clonazepam; clonitazene; 7-chloro-2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzodiazepine-3-carboxylic acid; clorazepate; 5-(2-chlorophenyl)-7-ethyl-1-methyl-1H-thieno[2,3-e][1,4]diazepin-2(3H)-one; clotiazepam; 10-chloro-11b-(2-chlorophenyl)-2,3,7,11b-tetrahydrooxazolo [3,2-d][1,4]benzodiazepin-6(5H)-one; cloxazolam; (−)-methyl-[3β-benzoyloxy-2β(1αH,5αH)-tropane carboxylate]; cocaine; (5α,6α)-7,8-didehydro-4,5-epoxy-3-methoxy-17-methylmorphinan-6-ol; 4,5α-epoxy-3-methoxy-17-methyl-7-morphinen-6α-ol; codeine; 5-(1-cyclohexenyl)-5-ethyl barbituric acid; cyclobarbital; cyclorphan; cyprenorphine; 7-chloro-5-(2-chlorophenyl)-1H-1,4-benzodiazepin-2(3H)-one; delorazepam; desomorphine; dextromoramide; (+)-(1-benzyl-3-dimethylamino-2-methyl-1-phenylpropyl)propionate; dextropropoxyphene; dezocine; diampromide; diamorphone; 7-chloro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2(3H)-on; diazepam; 4,5α-epoxy-3-methoxy-17-methyl-6α-morphinanol; dihydrocodeine; 4,5α-epoxy-17-methyl-3,6a-morphinandiol; dihydromorphine; dimenoxadol; dimephetamol; dimethylthiambutene; dioxaphetyl butyrate; dipipanone; (6aR,10aR)-6,6,9-trimethyl-3-pentyl-6a,7,8,10a-tetrahydro-6H-benzo[c]chromen-1-ol; dronabinol; eptazocine; 8-chloro-6-phenyl-4H-[1,2,4]-triazolo[4,3-(a)][1,4]benzodiazepine; estazolam; ethoheptazine; ethylmethylthiambutene; ethyl[7-chloro-5-(2-fluorophenyl)-2,3-dihydro-2-oxo-1H-1,4-benzodiazepine-3-carboxylate]; ethyl loflazepate; 4,5α-epoxy-3-ethoxy-17-methyl-7-morphinen-6α-ol; ethylmorphine; etonitazene; 4,5α-epoxy-7α-(1-hydroxy-1-methylbutyl)-6-methoxy-17-methyl-6,14-endo-etheno-morphinan-3-ol; etorphine; N-ethyl-3-phenyl-8,9,10-trinorbornan-2-ylamine; fencamfamine; 7-[2-(α-methylphenethylamino)ethyl]-theophylline; fenethylline; 3-(α-methylphenethylamino)propionitrile; fenproporex; N-(1-phenethyl-4-piperidyl)propionanilide; fentanyl; 7-chloro-5-(2-fluorophenyl)-1-methyl-1H-1,4-benzodiazepin-2(3H)-one; fludiazepam; 5-(2-fluorophenyl)-1-methyl-7-nitro-1H-1,4-benzodiazepin-2(3H)-one; flunitrazepam; 7-chloro-1-(2-diethylaminoethyl)-5-(2-fluorophenyl)-1H-1,4-benzodiazepin-2(3H)-one; flurazepam; 7-chloro-5-phenyl-1-(2,2,2-trifluoroethyl)-1H-1,4-benzodiazepin-2(3H)-one; halazepam; 10-bromo-11b-(2-fluorophenyl)-2,3,7,11b-tetrahydro[1,3]oxazolyl[3,2-d][1,4]benzodiazepin-6(5H)-one; haloxazolam; heroin; 4,5α-epoxy-3-methoxy-17-methyl-6-morphinanone; hydrocodone; 4,5α-epoxy-3-hydroxy-17-methyl-6-morphinanone; hydromorphone; hydroxypethidine; isomethadone; hydroxymethylmorphinan; 11-chloro-8,12b-dihydro-2,8-dimethyl-12b-phenyl-4H-[1,3]oxazino[3,2d][1,4]benzodiazepine-4,7(6H)-dione; ketazolam; 1-[4-(3-hydroxyphenyl)-1-methyl-4-piperidyl]-1-propanone; ketobemidone; (3S,6S)-6-dimethylamino-4,4-diphenylheptan-3-yl acetate; levacetylmethadol; LAAM; (−)-6-dimethylamino-4,4-diphenol-3-heptanone; levomethadone; (−)-17-methyl-3-morphinanol; levorphanol; levophenacylmorphane; lofentanil; 6-(2-chlorophenyl)-2-(4-methyl-1-piperazinylmethylene)-8-nitro-2H-imidazo[1,2-a][1,4]-benzodiazepin-1(4H)-one; loprazolam; 7-chloro-5-(2-chlorophenyl)-3-hydroxy-1H-1,4-benzodiazepin-2(3H)-one; lorazepam; 7-chloro-5-(2-chlorophenyl)-3-hydroxy-1-methyl-1H-1,4-benzodiazepin-2(3H)-one; lormetazepam; 5-(4-chlorophenyl)-2,5-dihydro-3H-imidazo[2,1a]isoindol-5-ol; mazindol; 7-chloro-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepine; medazepam; N-(3-chloropropyl)-α-methylphenethylamine; mefenorex; meperidine; 2-methyl-2-propyltrimethylene dicarbamate; meprobamate; meptazinol; metazocine; methylmorphine; N,α-dimethylphenethylamine; metamphetamine; (±)-6-dimethylamino-4,4-diphenol-3-heptanone; methadone; 2-methyl-3-o-tolyl-4(3H)-quinazolinone; methaqualone; methyl [2-phenyl-2-(2-piperidyl)acetate]; methylphenidate; 5-ethyl-1-methyl-5-phenylbarbituric acid; methylphenobarbital; 3,3-diethyl-5-methyl-2,4-piperidinedione; methyprylon; metopon; 8-chloro-6-(2-fluorophenyl)-1-methyl-4H-imidazo[1,5-a][1,4]benzodiazepine; midazolam; 2-(benzhydrylsulfinyl)acetamide; modafinil; (5α,6α)-7,8-didehydro-4,5-epoxy-17-methyl-7-methylmorphinan-3,6-diol; morphine; myrophine; (±)-trans-3-(1,1-dimethylheptyl)-7,8,10,10α-tetrahydro-1-hydroxy-6,6-dimethyl-6H-dibenzo-[b,d]pyran-9(6αH)one; nabilone; nalbuphene; nalorphine; narceine; nicomorphine; 1-methyl-7-nitro-5-phenyl-1H-1,4-benzodiazepin-2(3H)-one; nimetazepam; 7-nitro-5-phenyl-1H-1,4-benzodiazepin-2(3H)-one; nitrazepam; 7-chloro-5-phenyl-1H-1,4-benzodiazepin-2(-3H)-one; nordazepam; norlevorphanol; 6-dimethylamino-4,4-diphenyl-3-hexanone; normethadone; normorphine; norpipanone; opium; 7-chloro-3-hydroxy-5-phenyl-1H-1,4-benzodiazepin-2(3H)-one; oxazepam; (cis-/trans-)-10-chloro-2,3,7,11b-tetrahydro-2-methyl-11b-phenyloxazolo[3,2-d][1,4]benzodiazepin-6-(5H)-one; oxazolam; 4,5α-epoxy-14-hydroxy-3-methoxy-17-methyl-6-morphinanone; oxycodone; oxymorphone; papaveretum; 2-imino-5-phenyl-4-oxazolidinone; pernoline; 1,2,3,4,5,6-hexahydro-6,11-dimethyl-3-(3-methyl-2-butenyl)-2,6-methano-3-benzazocin-8-ol; pentazocine; 5-ethyl-5-(1-methylbutyl)-barbituric acid; pentobarbital; ethyl-(1-methyl-4-phenyl-4-piperidinecarboxylate); pethidine; phenadoxone; phenomorphane; phenazocine; phenoperidine; piminodine; pholcodeine; 3-methyl-2-phenylmorpholine; phenmetrazine; 5-ethyl-5-phenylbarbituric acid; phenobarbital; α,α-dimethylphenethylamine; phentermine; (R)-3-[-1-hydroxy-2-(methylamino)ethyl]phenol; phenylephrine, 7-chloro-5-phenyl-1-(2-propynyl)-1H-1,4-benzodiazepin-2(3H)-one; pinazepam; α-(2-piperidyl)benzhydryl alcohol; pipradrol; 1′-(3-cyano-3,3-diphenylpropyl)[1,4′-bipiperidine]-4′-carboxamide; piritramide; 7-chloro-1-(cyclopropylmethyl)-5-phenyl-1H-1,4-benzodiazepin-2(3H)-one; prazepam; profadol; proheptazine; promedol; properidine; propoxyphene; N-(1-methyl-2-piperidinoethyl)-N-(2-pyridyl)propionamide; methyl {3-[4-methoxycarbonyl-4-(N-phenylpropanamido)piperidino]propanoate}; (S,S)-2-methylamino-1-phenylpropan-1-ol; pseudoephedrine, remifentanil; 5-sec-butyl-5-ethylbarbituric acid; secbutabarbital; 5-allyl-5-(1-methylbutyl)-barbituric acid; secobarbital; N-{4-methoxymethyl-1-[2-(2-thienyl)ethyl]-4-piperidyl}propionanilide; sufentanil; 7-chloro-2-hydroxymethyl-5-phenyl-1H-1,4-benzodiazepin-2(3H)-one; temazepam; 7-chloro-5-(1-cyclohexenyl)-1-methyl-1H-1,4-benzodiazepin-2(3H)-one; tetrazepam; ethyl (2-dimethylamino-1-phenyl-3-cyclohexene-1-carboxylate; cis-/trans-tilidine; tramadol; 8-chloro-6-(2-chlorophenyl)-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine; triazolam; 5-(1-methylbutyl)-5-vinylbarbituric acid; vinylbital; (1R*,2R*)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)phenol; (1R,2R,4S)-2-(dimethylamino)methyl-4-(p-fluorobenzyloxy)-1-(m-methoxyphenyl)cyclohexanol; a prodrug thereof; a pharmaceutically acceptable salt thereof; an adduct thereof; and a solvate thereof.
 8. The parenteral abuse resistant capsule of claim 1, wherein the active pharmaceutical ingredient is selected from the group consisting of codeine, tramadol, anileridine, prodine, pethidine, hydrocodone, morphine, oxycodone, methadone, diamorphine, hydromorphone, oxymorphone, 7-hydroxymitragynine, buprenorphine, fentanyl, sufentanil, levorphanol, meperidine, dihydrocodeine, dihydromorphine, morphine, hydromorphone, oxymorphone, tilidine, a prodrug thereof, a pharmaceutically acceptable salt thereof, and a solvate thereof.
 9. The parenteral abuse resistant capsule of claim 1, that is resistant to alcohol dose dumping.
 10. The parenteral abuse resistant capsule of claim 1, that is resistant to solvent, acidic or aqueous extraction.
 11. The parenteral abuse resistant capsule of claim 1, wherein the capsule is a soft capsule.
 12. The parenteral abuse resistant capsule of claim 1, wherein the capsule is a hard gelatin capsule.
 13. The parenteral abuse resistant capsule of claim 1, wherein the surfactant comprises caprylocaproylmacrogol-8 glyceride.
 14. The parenteral abuse resistant capsule of claim 1, comprising at least 15 wt. % of the surfactant caprylocaproylmacrogol-8 glyceride.
 15. The parenteral abuse resistant capsule of claim 1, wherein the parenteral abuse resistant liquid does not contain a lipophilic carrier or lipophilic solvent.
 16. The parenteral abuse resistant capsule of claim 1, wherein the xanthan gum is present in the parenteral abuse-resistant liquid in an amount of 0.2 to 0.5 wt %.
 17. The parenteral abuse resistant capsule of claim 6, wherein the xanthan gum is present in the parenteral abuse-resistant liquid in an amount of 0.2 to 0.5 wt %.
 18. The parenteral abuse resistant capsule of claim 1, wherein upon heating or boiling the parenteral abuse resistant liquid with water, bubbles develop.
 19. The parenteral abuse resistant capsule of claim 1, wherein the hydrophilic carrier is macrogol 400, macrogol 600 or macrogol 1500, and optionally one or more of propylene glycol, glycerol, and water. 